Selective Inhibitors Of Protein Arginine Methytransterase 5 (PRMT5)

ABSTRACT

Pharmaceutical compositions comprising compounds of Formula I, as well as methods of their use and preparation, are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/059,909, filed Aug. 9, 2018, which claims the benefit of priority toU.S. Provisional Patent Application No. 62/543,141, filed Aug. 9, 2017,U.S. Provisional Patent Application No. 62/630,581, filed Feb. 14, 2018,and U.S. Provisional Patent Application No. 62/664,442, filed Apr. 30,2018. The entirety of each of these applications is incorporated byreference herein.

TECHNICAL FIELD

The disclosure is directed to PRMT5 inhibitors and methods of their use.

BACKGROUND

Protein arginine methylation is a common post-translational modificationthat regulates numerous cellular processes, including genetranscription, mRNA splicing, DNA repair, protein cellular localization,cell fate determination, and signaling. Three types of methyl-argininespecies exist: ω NG monomethylarginine (MMA), ω NG, NG asymmetricdimethylarginine (ADMA) and ω NG, N′G symmetric dimethylarginine (SDMA).The formation of methylated arginines is catalyzed by the proteinarginine methyl transferases (PRMTs) family of methyltransferases.Currently, there are nine PRMTs annotated in the human genome. Themajority of these enzymes are Type I enzymes (PRMT1, -2, -3, -4, -6, -8)that are capable of mono- and asymmetric dimethylation of arginine, withS-adenosylmethionine (SAM) as the methyl donor. PRMT-5, -7 and -9 areconsidered to be Type II enzymes that catalyze symmetric dimethylationof arginines. Each PRMT species harbors the characteristic motifs ofseven beta strand methyltransferases (Katz et al., 2003), as well asadditional “double E” and “THW” sequence motifs particular to the PRMTsubfamily.

PRMT5 is as a general transcriptional repressor that functions withnumerous transcription factors and repressor complexes, including BRG1and hBRM, Blimp1, and Snail. This enzyme, once recruited to a promoter,symmetrically dimethylates H3R8 and H4R3. Importantly, the H4R3 site isa major target for PRMT1 methylation (ADMA) and is generally regarded asa transcriptional activating mark. Thus, both H4R3me2s (repressive; me2sindicates SDMA modification) and H4R3me2a (active: me2a indicates ADMAmodification) marks are produced in vivo. The specificity of PRMT5 forH3R8 and H4R3 can be altered by its interaction with COPR5 and thiscould perhaps play an important role in determining PRMT5 corepressorstatus.

Role of PRMTs in Cancer

Aberrant expression of PRMTs has been identified in human cancers, andPRMTs are considered to be therapeutic targets. Global analysis ofhistone modifications in prostate cancer has shown that thedimethylation of histone H4R3 is positively correlated with increasinggrade, and these changes are predictive of clinical outcome.

PRMT5 levels have been shown to be elevated in a panel of lymphoidcancer cell lines as well as mantle cell lymphoma clinical samples.PRMT5 interacts with a number of substrates that are involved in avariety of cellular processes, including RNA processing, signaltransduction, and transcriptional regulation. PRMT5 can directly modifyhistone H3 and H4, resulting in the repression of gene expression. PRMT5overexpression can stimulate cell growth and induce transformation bydirectly repressing tumor suppressor genes. Pal et al., Mol. Cell. Biol.2003, 7475; Pal et al. Mol. Cell. Biol. 2004, 9630; Wang et al. Mol.Cell. Biol. 2008, 6262; Chung et al. J Biol Chem 2013, 5534. In additionto its well-documented oncogenic functions in transcription andtranslation, the transcription factor MYC also safeguards properpre-messenger-RNA splicing as an essential step in lymphomagenesis. Kohet al. Nature 2015, 523 7558; Hsu et al. Nature 2015 525, 384.

The discovery of cancer dependencies has the potential to informtherapeutic strategies and to identify putative drug targets.Integrating data from comprehensive genomic profiling of cancer celllines and from functional characterization of cancer cell dependencies,it has been recently discovered that loss of the enzymemethylthioadenosine phosphorylase (MTAP) confers a selective dependenceon protein arginine methyltransferase 5 (PRMT5) and its binding partnerWDR77. MTAP is frequently lost due to its proximity to the commonlydeleted tumor suppressor gene, CDKN2A. Cells harboring MTAP deletionspossess increased intracellular concentrations of methylthioadenosine(MTA, the metabolite cleaved by MTAP). Furthermore, MTA specificallyinhibits PRMT5 enzymatic activity. Administration of either MTA or asmall-molecule PRMT5 inhibitor shows a preferential impairment of cellviability for MTAP-null cancer cell lines compared to isogenicMTAP-expressing counterparts. Together, these findings reveal PRMT5 as apotential vulnerability across multiple cancer lineages augmented by acommon “passenger” genomic alteration.

Role of PRMT5 in Hemoglobinopathies

The developmental switch in human globin gene subtype from fetal toadult that begins at birth heralds the onset of the hemoglobinopathies,b-thalassemia and sickle cell disease (SCD). The observation thatincreased adult globin gene expression (in the setting of hereditarypersistence of fetal hemoglobin [HPFH] mutations) significantlyameliorates the clinical severity of thalassemia and SCD has promptedthe search for therapeutic strategies to reverse gamma-globin genesilencing. Central to silencing of the gamma-genes is DNA methylation,which marks critical CpG dinucleotides flanking the gene transcriptionalstart site in adult bone marrow erythroid cells. It has been shown thatthese marks are established as a consequence of recruitment of the DNAmethyltransferase, DNMT3A to the gamma-promoter by the protein argininemethyltransferase PRMT5. Zhao et al. Nat Struct Mol Biol. 2009 16, 304.PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, couplinghistone and DNA methylation in gene silencing.

PRMT5 induces the repressive histone mark, H4R3me2s, which serves as atemplate for direct binding of DNMT3A, and subsequent DNA methylation.Loss of PRMT5 binding or its enzymatic activity leads to demethylationof the CpG dinucleotides and gene activation. In addition to theH4R3me2s mark and DNA methylation, PRMT5 binding to the gamma-promoter,and its enzymatic activity are essential for assembly of a multiproteincomplex on the gamma-promoter, which induces a range of coordinatedrepressive epigenetic marks. Disruption of this complex leads toreactivation of gamma gene expression. These studies provide the basisfor developing PRMT5 inhibitors as targeted therapies for thalassemiaand SCD.

SUMMARY

The disclosure is directed to compounds of Formula I:

or a pharmaceutically acceptable salt or solvate thereof;

wherein

-   -   R¹ is —C₀-C₆alk-C₁-C₆alkyl, —C₀-C₆alk-C₁-C₆haloalkyl,        —C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₆alk-S—C₁-C₆alkyl,        —C₁-C₆alk-S—C₁-C₆alk-CO₂H, —C₁-C₆alk-aryl, —C₁-C₆alk-O-aryl,        —C₁-C₆alk-NH-aryl, —C₁-C₆alk-S-aryl, —C₀-C₆alk-heteroaryl,        —C₁-C₆alk-O-heteroaryl, —C₁-C₆alk-S-heteroaryl,        —C₁-C₆alk-NH-heteroaryl, or —C(O)NH-aryl;    -   R² is —C₁-C₆alkyl, —C₁-C₆haloalkyl, —C₂-C₆alkenyl, or        —C₂-C₆alkynyl;    -   R³ is H, halo, NH₂, or —C₁-C₆alkyl;    -   R⁴ is H, halo, —C₁-C₆alkyl, —C₁-C₆alk-O—C₁-C₆alkyl, —NR⁶R^(6′),        —NHC(O)NR⁶R^(6′), —NHC(S)NR⁶R^(6′), —NH—O—R⁶, or —NH—NR⁶R^(6′);    -   R⁵ is H, halo, —C₁-C₆alkyl, —C₁-C₆haloalkyl, —C₂-C₆alkenyl,        —C₂-C₆alkynyl, or —C₁-C₆alk-OH; and    -   R⁶ and R^(6′) are each independently H, C₁-C₆alkyl, or        —C₁-C₆alk-OC₁-C₆alkyl;    -   or R⁶ and R^(6′), together with the atom to which they are        attached, form a C₃-C₆heterocycloalkyl ring.

Stereoisomers of the compounds of Formula I, and the pharmaceuticalsalts and solvates thereof, are also described. Methods of usingcompounds of Formula I are described, as well as pharmaceuticalcompositions including the compounds of Formula I.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The disclosure may be more fully appreciated by reference to thefollowing description, including the following definitions and examples.Certain features of the disclosed compositions and methods which aredescribed herein in the context of separate aspects, may also beprovided in combination in a single aspect. Alternatively, variousfeatures of the disclosed compositions and methods that are, forbrevity, described in the context of a single aspect, may also beprovided separately or in any subcombination.

The term “alkyl,” when used alone or as part of a substituent group,refers to a straight- or branched-chain hydrocarbon group having from 1to 12 carbon atoms (“C₁-C₁₂”), preferably 1 to 6 carbons atoms(“C₁-C₆”), in the group. Examples of alkyl groups include methyl (Me,C₁alkyl), ethyl (Et, C₂alkyl), n-propyl (C₃alkyl), isopropyl (C₃alkyl),butyl (C₄alkyl), isobutyl (C₄alkyl), sec-butyl (C₄alkyl), tert-butyl(C₄alkyl), pentyl (C₅alkyl), isopentyl (C₅alkyl), tert-pentyl (C₅alkyl),hexyl (C₆alkyl), isohexyl (C₆alkyl), and the like.

The term “halo” when used alone or as part of a substituent group refersto chloro, fluoro, bromo, or iodo.

The term “haloalkyl” when used alone or as part of a substituent grouprefers to an alkyl group wherein one or more of the hydrogen atoms hasbeen replaced with one or more halogen atoms. Halogen atoms includechlorine, fluorine, bromine, and iodine. Examples of haloalkyl groups ofthe disclosure include, for example, trifluoromethyl (—CF₃),chloromethyl (—CH₂Cl), and the like.

The term “cycloalkyl” when used alone or as part of a substituent grouprefers to cyclic-containing, non-aromatic hydrocarbon groups having from3 to 10 carbon atoms (“C₃-C₁₀”), preferably from 3 to 6 carbon atoms(“C₃-C₆”). Examples of cycloalkyl groups include, for example,cyclopropyl (C₃), cyclobutyl (C₄), cyclopropylmethyl (C₄), cyclopentyl(C₅), cyclohexyl (C₆), 1-methylcyclopropyl (C₄), 2-methylcyclopentyl(C₄), adamantanyl (C₁₀), and the like.

The term “heterocycloalkyl” when used alone or as part of a substituentgroup refers to any three to ten membered monocyclic or bicyclic,saturated ring structure containing at least one heteroatom selectedfrom the group consisting of O, N and S. The heterocycloalkyl group maybe attached at any heteroatom or carbon atom of the ring such that theresult is a stable structure. Examples of suitable heterocycloalkylgroups include, but are not limited to, azepanyl, aziridinyl,azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl,piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl,thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl,tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, and the like.

The term “alkenyl” when used alone or as part of a substituent grouprefers to a straight- or branched-chain group having from 2 to 12 carbonatoms (“C₂-C₁₂”), preferably 2 to 4 carbons atoms (“C₂-C₄”), in thegroup, wherein the group includes at least one carbon-carbon doublebond. Examples of alkenyl groups include vinyl (—CH═CH₂; C₂alkenyl)allyl (—CH₂—CH═CH₂; C₃alkenyl), propenyl (—CH═CHCH₃; C₃alkenyl);isopropenyl (—C(CH₃)═CH₂; C₃alkenyl), butenyl (—CH═CHCH₂CH₃; C₄alkenyl),sec-butenyl (—C(CH₃)═CHCH₃; C₄alkenyl), iso-butenyl (—CH═C(CH₃)₂;C₄alkenyl), 2-butenyl (—CH₂CH═CHCH₃; C₄alkyl), pentenyl(—CH═CHCH₂CH₂CH₃; C₅alkenyl), and the like.

The term “alkynyl” when used alone or as part of a substituent grouprefers to a straight- or branched-chain group having from 1 to 12 carbonatoms (“C₁-C₁₂”), preferably 1 to 4 carbons atoms (“C₂-C₄”), in thegroup, and wherein the group includes at least one carbon-carbon triplebond. Examples of alkynyl groups include ethynyl (—C≡CH; C₂alkynyl);propargyl (—CH₂—C≡CH; C₃alkynyl), propynyl (—C≡CCH₃; C₃alkynyl); butynyl(—C≡CCH₂CH₃; C₄alkynyl), pentynyl (—C≡CCH₂CH₂CH₃; C₅alkynyl), and thelike.

The term “aryl” when used alone or as part of a substituent group refersto a mono- or bicyclic-aromatic hydrocarbon ring structure having 6 or10 carbon atoms in the ring, wherein one or more of the carbon atoms inthe ring is optionally substituted with a halogen atom, a —C₁-C₃ alkylgroup, an amino-substituted —C₁-C₃ alkyl group, a C₁-C₃haloalkyl group,an amino group (i.e., —NH₂), or a substituted amino group. The term“aryl” when used alone or as part of a substituent group also refers toa mono- or bicyclic-aromatic hydrocarbon ring structure having 6 or 10carbon atoms in the ring, wherein one or more of the carbon atoms in thering is optionally substituted with a halogen atom, a —C₁-C₃ alkylgroup, an amino-substituted —C₁-C₃ alkyl group, analkylamino-substituted —C₁-C₃ alkyl group, a hydroxy-substituted —C₁-C₃alkyl group, a C₁-C₃haloalkyl group, an —O—C₁-C₃haloalkyl group, anamino group (i.e., —NH₂), or a substituted amino group. Halogen atomsinclude chlorine, fluorine, bromine, and iodine. Amino-substituted—C₁-C₃ alkyl groups include —CH₂—NH₂, —CH₂CH₂—NH₂, and the like.Alkylamino-substituted —C₁-C₃ alkyl groups include —CH₂—NHCH₃ and thelike. C₁-C₃haloalkyl groups include, for example, —CF₃, —CH₂CF₃, and thelike. Substituted amino groups include, for example, —NH—C(O)—NH₂.Hydroxy-substituted —C₁-C₃ alkyl groups include —CH₂—OH and the like.The term “aryl” also includes a mono- or bicyclic-aromatic hydrocarbonring structure having 6 or 10 carbon atoms in the ring, wherein twoadjacent carbon atoms in the ring are optionally substituted such thatsaid two adjacent carbon atoms and their respective substituents form aheterocyclic ring. Thus, aryl groups include, for example,2,3-dihydrobenzofuran and 1,3-benzodioxole. Examples of aryl groups(substituted and unsubstituted) include phenyl, aminomethylphenyl,3-(aminomethyl)phenyl, phenylurea, methylchlorophenyl,3-methyl-4-chlorophenyl, fluorochlorophenyl, 3-fluoro-4-chlorophenyl,naphtyl, fluorophenyl, trifluoromethylphenyl, 4-trifluoromethylphenyl,fluoro-triflouromethylphenyl, 3-fluoro-4-trifluoromethylphenyl,4-fluoro-3-trifluoromethylphenyl, difluorophenyl, 3,4-difluorophenyl,chlorophenyl, 4-chlorophenyl, 4-chloro-2-(hydroxymethyl)phenyl,2-(aminomethyl)-4-chlorophenyl, 4-chloro-2-((methylamino)methyl)phenyl,dichlorophenyl, 3,4-dichlorophenyl, bromophenyl, iodophenyl,chlorofluorophenyl, fluoronaphthyl, difluoronaphthyl, chloronaphthyl,bromonaphthyl, iodonaphthyl, methylphenyl, ethylphenyl,4-isopropylphenyl, 4-(trifluoromethoxy)phenyl, benzo[d][1,3]dioxolyl,and the like.

The term “heteroaryl” when used alone or as part of a substituent grouprefers to a mono- or bicyclic-aromatic ring structure including carbonatoms as well as up to four heteroatoms selected from nitrogen, oxygen,and sulfur. Heteroaryl rings can include a total of 5, 6, 9, or 10 ringatoms. The heteroaryl moiety can be unsubstituted, or one or more of thecarbon atoms in the ring can be substituted with a halogen atom; anamino group; a substituted amino group, including an amino groupsubstituted with a —C₁-C₆ cycloalkyl group, a —O—C₁-C₃alkyl group, or a—C₁-C₆ alkyl group; or a —C₁-C₃ alkyl group. Halogen atoms includechlorine, fluorine, bromine, and iodine. Examples of heteroaryl groupsinclude but are not limited to, pyrrolyl, furyl, thiophenyl (thienyl),oxazolyl, imidazolyl, purazolyl, isoxazolyl, isothiazolyl, triazolyl,thiadiazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyranyl, furazanyl, indolizinyl, indolyl, indol-6-yl, isoindolinyl,indazolyl, indazol-6-yl, benzofuranyl, benzothiophenyl, benzimidazolyl,benzthiazolyl, purinyl, quinolizinyl, quinolinyl, aminoquinolinyl,aminohaloquinolinyl, quinolin-7-yl, 2-amino-3-bromoquinolin-7-yl,2-amino-3-chloroquinolin-7-yl, 2-amino-3-fluoroquinolin-7-yl,2-((cyclopropylmethyl)amino)quinolin-7-yl, 2-(methylamino)quinolin-7-yl,2-(methoxyamino)quinolin-7-yl, 2-aminoquinolin-7-yl, isoquinolinyl,isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, imidazo[1,2-a]pyridinyl, substitutedimidazo[1,2-a]pyridinyl, 3-methylimidazo[1,2-a]pyridin-7-yl, and thelike.

When a range of carbon atoms is used herein, for example, C₁-C₆, allranges, as well as individual numbers of carbon atoms are encompassed.For example, “C₁-C₃” includes C₁-C₃, C₁-C₂, C₂-C₃, C₁, C₂, and C₃.

The term “C₁-C₆alk” when used alone or as part of a substituent grouprefers to an aliphatic linker having 1, 2, 3, 4, 5, or 6 carbon atomsand includes, for example, —CH₂—, —CH(CH₃)—, —CH(CH₃)—CH₂—, and—C(CH₃)₂—. The term “—C₀alk-” refers to a bond. In some aspects, theC₁-C₆alk can be substituted with one or more —OH, —NH₂, or halo (e.g.,—F, —Cl, —Br, with —F being preferred) substituents.

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or a state government or thecorresponding agency in countries other than the United States, or thatis listed in the U.S. Pharmacopoeia or other generally recognizedpharmacopoeia for use in animals, e.g., in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of thedisclosure that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. In particular,such salts are non-toxic may be inorganic or organic acid addition saltsand base addition salts. Specifically, such salts include: (1) acidaddition salts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or formed with organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non-toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluent to facilitate administration of an agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols.

A “solvate” refers to a physical association of a compound of Formula Iwith one or more solvent molecules.

“Subject” includes humans. The terms “human,” “patient,” and “subject”are used interchangeably herein.

“Treating” or “treatment” of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In another embodiment “treating” or “treatment”refers to ameliorating at least one physical parameter, which may not bediscernible by the subject. In yet another embodiment, “treating” or“treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically. (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers to delayingthe onset of the disease or disorder.

“Compounds of the present disclosure,” and equivalent expressions, aremeant to embrace compounds of Formula I as described herein, as well astheir subgenera, which expression includes the stereoisomers (e.g.,entaniomers, diastereomers) and constitutional isomers (e.g., tautomers)of compounds of Formula I as well as the pharmaceutically acceptablesalts, where the context so permits.

As used herein, the term “isotopic variant” refers to a compound thatcontains proportions of isotopes at one or more of the atoms thatconstitute such compound that is greater than natural abundance. Forexample, an “isotopic variant” of a compound can be radiolabeled, thatis, contain one or more radioactive isotopes, or can be labeled withnon-radioactive isotopes such as for example, deuterium (²H or D),carbon-13 (¹³C), nitrogen-15 (¹⁵N), or the like. It will be understoodthat, in a compound where such isotopic substitution is made, thefollowing atoms, where present, may vary, so that for example, anyhydrogen may be ²H/D, any carbon may be ¹³C, or any nitrogen may be ¹⁵N,and that the presence and placement of such atoms may be determinedwithin the skill of the art.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers.” Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers,” for example, diastereomers, enantiomers, andatropisomers. The compounds of this disclosure may possess one or moreasymmetric centers; such compounds can therefore be produced asindividual (R)- or (S)-stereoisomers at each asymmetric center, or asmixtures thereof. Unless indicated otherwise, the description or namingof a particular compound in the specification and claims is intended toinclude all stereoisomers and mixtures, racemic or otherwise, thereof.Where one chiral center exists in a structure, but no specificstereochemistry is shown for that center, both enantiomers, individuallyor as a mixture of enantiomers, are encompassed by that structure. Wheremore than one chiral center exists in a structure, but no specificstereochemistry is shown for the centers, all enantiomers anddiastereomers, individually or as a mixture, are encompassed by thatstructure. The methods for the determination of stereochemistry and theseparation of stereoisomers are well-known in the art.

The disclosure is directed to compounds of Formula I:

According to the disclosure, R¹ in Formula I is R¹—C₀-C₆alk-C₁-C₆alkyl,—C₀-C₆alk-C₁-C₆haloalkyl, —C₁-C₆alk-O—C₁-C₆alkyl,—C₁-C₆alk-S—C₁-C₆alkyl, —C₁-C₆alk-S—C₁-C₆alk-CO₂H, —C₁-C₆alk-aryl,—C₁-C₆alk-O-aryl, —C₁-C₆alk-NH-aryl, —C₁-C₆alk-S-aryl,—C₀-C₆alk-heteroaryl, —C₁-C₆alk-O-heteroaryl, —C₁-C₆alk-S-heteroaryl, or—C₁-C₆alk-NH-heteroaryl. In some aspects, R¹ is —C₀-C₆alk-C₁-C₆alkyl,—C₀-C₆alk-C₁-C₆haloalkyl, —C₁-C₆alk-O—C₁-C₆alkyl,—C₁-C₆alk-S—C₁-C₆alkyl, —C₁-C₆alk-S—C₁-C₆alk-CO₂H, —C₁-C₆alk-aryl,—C₁-C₆alk-O-aryl, —C₁-C₆alk-NH-aryl, —C₁-C₆alk-S-aryl,—C₀-C₆alk-heteroaryl, —C₁-C₆alk-O-heteroaryl, —C₁-C₆alk-S-heteroaryl,—C₁-C₆alk-NH-heteroaryl, or —C(O)NH-aryl.

In some aspects, R¹ is —C₀-C₆alk-C₁-C₆alkyl, for example,—C₀alk-C₁alkyl, —C₁alk-C₁alkyl, —C₂alk-C₁alkyl, —C₃alk-C₁alkyl,—C₄alk-C₁alkyl, —C₅alk-C₁alkyl, —C₆alk-C₁alkyl, —C₀alk-C₂alkyl,—C₁alk-C₂alkyl, —C₂alk-C₂alkyl, —C₃alk-C₂alkyl, —C₄alk-C₂alkyl,—C₅alk-C₂alkyl, —C₆alk-C₂alkyl, —C₀alk-C₃alkyl, —C₁alk-C₃alkyl,—C₂alk-C₃alkyl, —C₆alk-C₃alkyl, —C₄alk-C₃alkyl, —C₅alk-C₃alkyl,—C₆alk-C₃alkyl, —C₀alk-C₄alkyl, —C₁alk-C₄alkyl, —C₂alk-C₄alkyl,—C₃alk-C₄alkyl, —C₄alk-C₄alkyl, —C₁alk-C₄alkyl, —C₆alk-C₄alkyl,—C₀alk-C₅alkyl, —C₁alk-C₅alkyl, —C₂alk-C₅alkyl, —C₃alk-C₆alkyl,—C₄alk-C₅alkyl, —C₅alk-C₅alkyl, —C₆alk-C₅alkyl, —C₆alk-C₆alkyl,—C₁alk-C₆alkyl, —C₂alk-C₆alkyl, —C₃alk-C₆alkyl, —C₄alk-C₆alkyl,—C₅alk-C₆alkyl, —C₆alk-C₆alkyl, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, s-butyl, t-butyl, pentyl, —CH(OH)—C₁-C₆alkyl (for example,—CH(OH)— methyl, —CH(OH)-ethyl, —CH(OH)-propyl, —CH(OH)-isopropyl,—CH(OH)-pentyl, —CH(OH)-butyl, and the like), —CH(F)—C₁-C₆alkyl,—CH(NH₂)—C₁-C₆alkyl, —CH(Me)-C₁-C₆alkyl, —C(Me)(OH)—C₁-C₆alkyl, and thelike.

In other aspects, R¹ is —C₀-C₆alk-C₁-C₆haloalkyl, for example,—C₀alk-C₁haloalkyl, —C₁alk-C₁haloalkyl, —C₂alk-C₁haloalkyl,—C₃alk-C₁haloalkyl, —C₄alk-C₁haloalkyl, —C₅alk-C₁haloalkyl,—C₆alk-C₁haloalkyl, —C₀alk-C₂haloalkyl, —C₁alk-C₂haloalkyl,—C₂alk-C₂haloalkyl, —C₃alk-C₂haloalkyl, —C₄alk-C₂haloalkyl,—C₅alk-C₂haloalkyl, —C₆alk-C₂haloalkyl, —C₀alk-C₃haloalkyl,—C₁alk-C₃haloalkyl, —C₂alk-C₃haloalkyl, —C₃alk-C₃haloalkyl,—C₄alk-C₃haloalkyl, —C₅alk-C₃haloalkyl, —C₆alk-C₃haloalkyl,—C₀alk-C₄haloalkyl, —C₁alk-C₄haloalkyl, —C₂alk-C₄haloalkyl,—C₃alk-C₄haloalkyl, —C₄alk-C₄haloalkyl, —C₅alk-C₄haloalkyl,—C₆alk-C₄haloalkyl, —C₀alk-C₅haloalkyl, —C₁alk-C₅haloalkyl,—C₂alk-C₅haloalkyl, —C₃alk-C₅haloalkyl, —C₄alk-C₅haloalkyl,—C₅alk-C₅haloalkyl, —C₆alk-C₅haloalkyl, —C₀alk-C₆haloalkyl,—C₁alk-C₆haloalkyl, —C₂alk-C₆haloalkyl, —C₃alk-C₆haloalkyl,—C₄alk-C₆haloalkyl, —C₅alk-C₆haloalkyl, —C₀alk-C₆haloalkyl,fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, fluoropentyl,chloromethyl, chloroethyl, chloropropyl, chlorobutyl, chloropentyl,bromomethyl, bromoethyl, bromopropyl, bromobutyl, bromopentyl,iodomethyl, iodoethyl, iodopropyl, iodobutyl, iodopentyl, —CH(OH)—C₁-C₆haloalkyl (e.g., —CH(OH)-fluoromethyl, —CH(OH)-fluoroethyl,—CH(OH)-fluoropropyl, —CH(OH)— fluoroisopropyl, —CH(OH)-fluoropentyl,—CH(OH)-fluorobutyl), —CH(F)—C₁-C₆haloalkyl, —CH(NH₂)—C₁-C₆ haloalkyl,—CH(Me)-C₁-C₆ haloalkyl, —C(Me)(OH)—C₁-C₆ haloalkyl, and the like. Thus,in some aspects, R¹ is chloromethyl (i.e., —CH₂—Cl.)

In some aspects, R¹ is —C₁-C₆alk-O—C₁-C₆alkyl, for example,—C₁alk-O—C₁alkyl, —C₂alk-O—C₁alkyl, —C₃alk-O—C₁alkyl, —C₄alk-O—C₁alkyl,—C₅alk-O—C₁alkyl, —C₆alk-O—C₁alkyl, —C₁alk-O—C₂alkyl, —C₂alk-O—C₂alkyl,—C₃alk-O—C₂alkyl, —C₄alk-O—C₂alkyl, —C₅alk-O—C₂alkyl, —C₆alk-O—C₂alkyl,—C₁alk-O—C₃alkyl, —C₂alk-O—C₃alkyl, —C₃alk-O—C₃alkyl, —C₄alk-O—C₃alkyl,—C₅alk-O—C₃alkyl, —C₆alk-O—C₃alkyl, —C₁alk-O—C₄alkyl, —C₂alk-O—C₄alkyl,—C₃alk-O—C₄alkyl, —C₄alk-O—C₄alkyl, —C₅alk-O—C₄alkyl, —C₆alk-O—C₄alkyl,—C₁alk-O—C₅alkyl, —C₂alk-O—C₅alkyl, —C₃alk-O—C₅alkyl, —C₄alk-O—C₅alkyl,—C₅alk-O—C₅alkyl, —C₆alk-O—C₅alkyl, —C₁alk-O—C₆alkyl, —C₂alk-O—C₆alkyl,—C₃alk-O—C₆alkyl, —C₄alk-O—C₆alkyl, —C₅alk-O—C₆alkyl, or—C₆alk-O—C₆alkyl. In some embodiments, R¹ is —CH₂—O—CH₃.

In some aspects, R¹ is —C₁-C₆alk-S—C₁-C₆alkyl, for example,—C₁alk-S—C₁alkyl, —C₂alk-S—C₁alkyl, —C₃alk-S—C₁alkyl, —C₄alk-S—C₁alkyl,—C₅alk-S—C₁alkyl, —C₆alk-S—C₁alkyl, —C₁alk-S—C₂alkyl, —C₂alk-S—C₂alkyl,—C₃alk-S—C₂alkyl, —C₄alk-S—C₂alkyl, —C₅alk-S—C₂alkyl, —C₆alk-S—C₂alkyl,—C₁alk-S—C₃alkyl, —C₂alk-S—C₃alkyl, —C₃alk-S—C₃alkyl, —C₄alk-S—C₃alkyl,—C₅alk-S—C₃alkyl, —C₆alk-S—C₃alkyl, —C₁alk-S—C₄alkyl, —C₂alk-S—C₄alkyl,—C₃alk-S—C₄alkyl, —C₄alk-S—C₄alkyl, —C₅alk-S—C₄alkyl, —C₆alk-S—C₄alkyl,—C₁alk-S—C₅alkyl, —C₂alk-S—C₅alkyl, —C₃alk-S—C₅alkyl, —C₄alk-S—C₅alkyl,—C₅alk-S—C₅alkyl, —C₆alk-S—C₅alkyl, —C₁alk-S—C₆alkyl, —C₂alk-S—C₆alkyl,—C₃alk-S—C₆alkyl, —C₄alk-S—C₆alkyl, —C₅alk-S—C₆alkyl, or—C₆alk-S—C₆alkyl. In some embodiments, R¹ is —CH₂—S—CH₃.

In some aspects, R¹ is —C₁-C₆alk-S—C₁-C₆alk-CO₂H, for example,—C₁alk-S—C₁-C₆alk-CO₂H, —C₂alk-S—C₁-C₆alk-CO₂H, —C₃alk-S—C₁-C₆alk-CO₂H,—C₄alk-S—C₁-C₆alk-CO₂H, —C₅alk-S—C₁-C₆alk-CO₂H, —C₆alk-S—C₁-C₆alk-CO₂H,—C₁-C₆alk-S—C₁alk-CO₂H, —C₁-C₆alk-S—C₂alk-CO₂H, —C₁-C₆alk-S—C₃alk-CO₂H,—C₁-C₆alk-S—C₄alk-CO₂H, —C₁-C₆alk-S—C₅alk-CO₂H, —C₁-C₆alk-S—C₆alk-CO₂H,and the like. In some embodiments, R¹ is —CH₂—S—CH₂CH₂CH(NH₂)—CO₂H.

In some aspects, R¹ is —C₁-C₆alk-aryl, for example, —C₁alk-aryl,—C₂alk-aryl, —C₃alk-aryl, —C₄alk-aryl, —C₅alk-aryl, —C₆alk-aryl,—CH₂aryl, —CH(OH)-aryl, —CH(F)-aryl, —CH(NH₂)-aryl, —CH(Me)-aryl,—C(Me)(OH)-aryl, and the like.

In some embodiments wherein R¹ is —C₁-C₆alk-aryl, the -aryl is a mono-or bicyclic-aromatic hydrocarbon ring structure having 6 or 10 carbonatoms in the ring, wherein one or more of the carbon atoms in the ringis optionally substituted with a halogen atom, a —C₁-C₃ alkyl group, anamino-substituted —C₁-C₃ alkyl group, a C₁-C₃haloalkyl group, an aminogroup (i.e., —NH₂), or a substituted amino group.

In other embodiments wherein R¹ is —C₁-C₆alk-aryl, the -aryl is a mono-or bicyclic-aromatic hydrocarbon ring structure having 6 or 10 carbonatoms in the ring, wherein one or more of the carbon atoms in the ringis optionally substituted with a halogen atom, a —C₁-C₃ alkyl group, anamino-substituted —C₁-C₃ alkyl group, an alkylamino-substituted —C₁-C₃alkyl group, a hydroxy-substituted —C₁-C₃ alkyl group, a C₁-C₃haloalkylgroup, an —O—C₁-C₃haloalkyl group, an amino group (i.e., —NH₂), or asubstituted amino group.

In some embodiments wherein R¹ is —C₁-C₆alk-aryl, the -aryl is-4-chlorophenyl, 4-chloro-2-(hydroxymethyl)phenyl,4-chloro-2-(aminomethyl)phenyl, 4-chloro-2-((methylamino)methyl)phenyl,-3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro-4-chlorophenyl,3-methyl-4-chlorophenyl, 3-fluoro-4-trifluoromethylphenyl,4-trifluoromethylphenyl, 4-(trifluoromethoxy)phenyl,4-fluoro-3-trifluoromethylphenyl, benzo[d][1,3]dioxazole,4-isopropylphenyl, or -3-chloro-4-fluorophenyl. Thus in someembodiments, R¹ is —CH₂-difluorophenyl, —CH₂-3,4-difluorophenyl,—CH₂-4-chlorophenyl, —CH₂-(4-chloro-2-(hydroxymethyl)phenyl),—CH₂-(4-chloro-2-(aminomethyl)phenyl),—CH₂-(4-chloro-2-((methylamino)methyl)phenyl),—CH₂-3-chloro-4-fluorophenyl, —CH₂-4-chloro-3-fluorophenyl,—CH₂-dichlorophenyl, —CH₂-3,4-dichlorophenyl, —CH₂-3,4-difluorophenyl,—CH₂-3-methyl-4-chlorophenyl, —CH₂-4-trifluoromethylphenyl,—CH₂-4-(trifluoromethoxy)phenyl, —CH₂-3-fluoro-4-trifluoromethylphenyl,—CH₂-4-fluoro-3-trifluoromethylphenyl, benzo[d][1,3]dioxazol-5-ylmethyl,—CH₂-4-isopropylphenyl, —CH(OH)-4-chlorophenyl,—CH(OH)-4-chloro-2-(hydroxymethyl)phenyl,—CH(OH)-4-chloro-2-(aminomethyl)phenyl,—CH(OH)-4-chloro-2-((methylamino)methyl)phenyl,—CH(OH)-3,4-dichlorophenyl, —CH(OH)-3,4-difluorophenyl,—CH(OH)-3-fluoro-4-chlorophenyl, —CH(OH)-3-chloro-4-fluorophenyl,—CH(OH)-3-methyl-4-chlorophenyl, —CH(OH)-4-trifluoromethylphenyl,—CH(OH)-4-(trifluoromethoxy)phenyl,—CH(OH)-3-fluoro-4-trifluoromethylphenyl,—CH(OH)-4-fluoro-3-trifluoromethylphenyl,—CH(OH)-benzo[d][1,3]dioxazol-5-yl, —CH(OH)-4-isopropylphenyl,—CH(F)-4-chlorophenyl, —CH(F)-4-chloro-2-(hydroxymethyl)phenyl,—CH(F)-4-chloro-2-(aminomethyl)phenyl,—CH(F)-4-chloro-2-((methylamino)methyl)phenyl,—CH(F)-3,4-dichlorophenyl, —CH(F)-3,4-difluorophenyl,—CH(F)-3-fluoro-4-chlorophenyl, —CH(F)-3-chloro-4-fluorophenyl,—CH(F)-3-methyl-4-chlorophenyl, —CH(F)-4-trifluoromethylphenyl,—CH(F)-4-(trifluoromethoxy)phenyl,—CH(F)-3-fluoro-4-trifluoromethylphenyl,—CH(F)-4-fluoro-3-trifluoromethylphenyl,—CH(F)-benzo[d][1,3]dioxazol-5-yl, —CH(F)-4-isopropylphenyl,—CH(NH₂)-4-chlorophenyl, —CH(NH₂)-4-chloro-2-(hydroxymethyl)phenyl,—CH(NH₂)-4-chloro-2-(aminomethyl)phenyl,—CH(NH₂)-4-chloro-2-((methylamino)methyl)phenyl,—CH(NH₂)-3,4-dichlorophenyl, —CH(NH₂)-3,4-difluorophenyl,—CH(NH₂)-3-fluoro-4-chlorophenyl, —CH(NH₂)-3-chloro-4-fluorophenyl,—CH(NH₂)-3-methyl-4-chlorophenyl, —CH(NH₂)-4-trifluoromethylphenyl,—CH(NH₂)-4-(trifluoromethoxy)phenyl,—CH(NH₂)-3-fluoro-4-trifluoromethylphenyl,—CH(NH₂)-4-fluoro-3-trifluoromethylphenyl,—CH(NH₂)-benzo[d][1,3]dioxazol-5-yl, —CH(NH₂)-4-isopropylphenyl,—CH(Me)-4-chlorophenyl, —CH(Me)-4-chloro-2-(hydroxymethyl)phenyl,—CH(Me)-4-chloro-2-(aminomethyl)phenyl,—CH(Me)-4-chloro-2-((methylamino)methyl)phenyl,—CH(Me)-3,4-dichlorophenyl, —CH(Me)-3,4-difluorophenyl,—CH(Me)-3-fluoro-4-chlorophenyl, —CH(Me)-3-chloro-4-fluorophenyl,—CH(Me)-3-methyl-4-chlorophenyl, —CH(Me)-4-trifluoromethylphenyl,—CH(Me)-4-(trifluoromethoxy)phenyl,—CH(Me)-3-fluoro-4-trifluoromethylphenyl,—CH(Me)-4-fluoro-3-trifluoromethylphenyl,—CH(Me)-benzo[d][1,3]dioxazol-5-yl, —CH(Me)-4-isopropylphenyl,—C(Me)(OH)-4-chlorophenyl, —C(Me)(OH)-4-chloro-2-(hydroxymethyl)phenyl,—C(Me)(OH)-4-chloro-2-(aminomethyl)phenyl,—C(Me)(OH)-4-chloro-2-((methylamino)methyl)phenyl,—C(Me)(OH)-3,4-dichlorophenyl, —C(Me)(OH)-3,4-difluorophenyl,—C(Me)(OH)-3-fluoro-4-chlorophenyl, —C(Me)(OH)-3-chloro-4-fluorophenyl,—C(Me)(OH)-3-methyl-4-chlorophenyl, —C(Me)(OH)-4-trifluoromethylphenyl,—C(Me)(OH)-4-(trifluoromethoxy)phenyl,—C(Me)(OH)-3-fluoro-4-trifluoromethyl phenyl,—C(Me)(OH)-4-fluoro-3-trifluoromethylphenyl,—C(Me)(OH)-4-isopropylphenyl, or —C(Me)(OH)-benzo[d][1,3]dioxazol-5-yl.

In some embodiments wherein R¹ is —C₁-C₆alk-aryl, the -aryl is-4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl,-3-fluoro-4-chlorophenyl, 3-methyl-4-chlorophenyl,3-fluoro-4-trifluoromethylphenyl, benzo[d][1,3]dioxazole, or-3-chloro-4-fluorophenyl. Thus in some embodiments, R¹ is—CH₂-difluorophenyl, —CH₂-3,4-difluorophenyl, —CH₂-4-chlorophenyl,—CH₂-3-chloro-4-fluorophenyl, —CH₂-4-chloro-3-fluorophenyl,—CH₂-dichlorophenyl, —CH₂-3,4-dichlorophenyl,—CH₂-3-methyl-4-chlorophenyl, —CH₂-3-fluoro-4-trifluoromethylphenyl,benzo[d][1,3]dioxazol-5-ylmethyl, —CH(OH)-4-chlorophenyl.—CH(OH)-3,4-dichlorophenyl, —CH(OH)-3,4-difluorophenyl,—CH(OH)-3-fluoro-4-chlorophenyl, —CH(OH)-3-chloro-4-fluorophenyl,—CH(OH)-3-methyl-4-chlorophenyl,—CH(OH)-3-fluoro-4-trifluoromethylphenyl,—CH(OH)-benzo[d][1,3]dioxazol-5-yl, —CH(F)-4-chlorophenyl,—CH(F)-3,4-dichlorophenyl, —CH(F)-3,4-difluorophenyl,—CH(F)-3-fluoro-4-chlorophenyl, —CH(F)-3-chloro-4-fluorophenyl,—CH(F)-3-methyl-4-chlorophenyl, —CH(F)-3-fluoro-4-trifluoromethylphenyl,—CH(F)-benzo[d][1,3]dioxazol-5-yl, —CH(NH₂)-4-chlorophenyl,—CH(NH₂)-3,4-dichlorophenyl, —CH(NH-2)-3,4-difluorophenyl,—CH(NH₂)-3-fluoro-4-chlorophenyl, —CH(NH₂)-3-chloro-4-fluorophenyl,—CH(NH₂)-3-methyl-4-chlorophenyl,—CH(NH₂)-3-fluoro-4-trifluoromethylphenyl,—CH(NH₂)-benzo[d][1,3]dioxazol-5-yl, —CH(Me)-4-chlorophenyl,—CH(Me)-3,4-dichlorophenyl, —CH(Me)-3,4-difluorophenyl,—CH(Me)-3-fluoro-4-chlorophenyl, —CH(Me)-3-chloro-4-fluorophenyl,—CH(Me)-3-methyl-4-chlorophenyl,—CH(Me)-3-fluoro-4-trifluoromethylphenyl,—CH(Me)-benzo[d][1,3]dioxazol-5-yl, —C(Me)(OH)-4-chlorophenyl,—C(Me)(OH)-3,4-dichlorophenyl, —C(Me)(OH)-3,4-difluorophenyl,—C(Me)(OH)-3-fluoro-4-chlorophenyl, —C(Me)(OH)-3-chloro-4-fluorophenyl,—C(Me)(OH)-3-methyl-4-chlorophenyl,—C(Me)(OH)-3-fluoro-4-trifluoromethylphenyl, or—C(Me)(OH)-benzo[d][1,3]dioxazol-5-yl.

In other embodiments wherein R¹ is —C₁-C₆alk-aryl, the -aryl is-4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl,-3-fluoro-4-chlorophenyl, 3-methyl-4-chlorophenyl,3-fluoro-4-trifluoromethylphenyl, or -3-chloro-4-fluorophenyl. Thus insome embodiments, R¹ is —CH₂-difluorophenyl, —CH₂-3,4-difluorophenyl,—CH₂-4-chlorophenyl, —CH₂-3-chloro-4-fluorophenyl,—CH₂-4-chloro-3-fluorophenyl, —CH₂-dichlorophenyl,—CH₂-3,4-dichlorophenyl, —CH₂-3-methyl-4-chlorophenyl,—CH₂-3-fluoro-4-trifluoromethylphenyl, —CH(OH)-4-chlorophenyl,—CH(OH)-3,4-dichlorophenyl, —CH(OH)-3,4-difluorophenyl,—CH(OH)-3-fluoro-4-chlorophenyl, —CH(OH)-3-chloro-4-fluorophenyl,—CH(OH)-3-methyl-4-chlorophenyl,—CH(OH)-3-fluoro-4-trifluoromethylphenyl, —CH(F)-4-chlorophenyl,—CH(F)-3,4-dichlorophenyl, —CH(F)-3,4-difluorophenyl,—CH(F)-3-fluoro-4-chlorophenyl, —CH(F)-3-chloro-4-fluorophenyl,—CH(F)-3-methyl-4-chlorophenyl, —CH(F)-3-fluoro-4-trifluoromethylphenyl,—CH(NH₂)-4-chlorophenyl, —CH(NH₂)-3,4-dichlorophenyl,—CH(NH₂)-3,4-difluorophenyl, —CH(NH₂)-3-fluoro-4-chlorophenyl,—CH(NH₂)-3-chloro-4-fluorophenyl, —CH(NH₂)-3-methyl-4-chlorophenyl,—CH(NH₂)-3-fluoro-4-trifluoromethylphenyl, —CH(Me)-4-chlorophenyl,—CH(Me)-3,4-dichlorophenyl, —CH(Me)-3,4-difluorophenyl,—CH(Me)-3-fluoro-4-chlorophenyl, —CH(Me)-3-chloro-4-fluorophenyl,—CH(Me)-3-methyl-4-chlorophenyl,—CH(Me)-3-fluoro-4-trifluoromethylphenyl, —C(Me)(OH)-4-chlorophenyl,—C(Me)(OH)-3,4-dichlorophenyl, —C(Me)(OH)-3,4-difluorophenyl,—C(Me)(OH)-3-fluoro-4-chlorophenyl, —C(Me)(OH)-3-chloro-4-fluorophenyl,—C(Me)(OH)-3-methyl-4-chlorophenyl, or—C(Me)(OH)-3-fluoro-4-trifluoromethylphenyl.

In some aspects, R¹ is —C₁-C₆alk-O-aryl, for example, —C₁alk-O-aryl,—C₂alk-O-aryl, —C₃alk-O-aryl, —C₄alk-O-aryl, —C₆alk-O-aryl,—C₆alk-O-aryl, —CH₂—O-aryl, and the like. In some embodiments wherein R¹is —C₁-C₆alk-O-aryl, the -aryl is -4-chlorophenyl, -3,4-dichlorophenyl,-3,4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3-methyl-4-chlorophenyl,3-fluoro-4-trifluoromethylphenyl, -3-chloro-4-fluorophenyl, -phenyl,-3-(aminomethyl)phenyl, 3-(urea)phenyl, 3-methyl-4-chlorophenyl,3-fluoro-4-chlorophenyl, -3-fluoro-4-trifluoromethylphenyl,difluorophenyl, chlorophenyl, 4-chlorophenyl, dichlorophenyl,3,4-dichlorophenyl, bromophenyl, iodophenyl, or chlorofluorophenyl. Thusin some embodiments, R¹ is —CH₂—O-phenyl, —CH₂—O-difluorophenyl,—CH₂—O-3,4-difluorophenyl, —CH₂—O-4-chlorophenyl,—CH₂—O-3-chloro-4-fluorophenyl, —CH₂—O-4-chloro-3-fluorophenyl,—CH₂—O-dichlorophenyl, —CH₂—O-3,4-dichlorophenyl,—CH₂—O-3-methyl-4-chlorophenyl, —CH₂—O-3-fluoro-4-trifluoromethylphenyl,—CH₂—O-3-(aminomethyl)phenyl, —CH₂—O-3-(urea)phenyl. In some embodimentswherein R¹ is —C₁-C₆alk-O-aryl, the -aryl is-4-chloro-2-(hydroxymethyl)phenyl, -4-chloro-2-(aminomethyl)phenyl,-4-chloro-2-((methylamino)methyl)phenyl, -4-trifluoromethylphenyl,-4-(trifluoromethoxy)phenyl, 4-fluoro-3-trifluoromethylphenyl, or-4-isopropylphenyl.

In some aspects, R¹ is —C₁-C₆alk-NH-aryl, for example, —C₁alk-NH-aryl,—C₂alk-NH-aryl, —C₃alk-NH-aryl, —C₄alk-NH-aryl, —C₅alk-NH-aryl,—C₆alk-NH-aryl, —CH₂—NH-aryl, and the like. In some embodiments whereinR¹ is —C₁-C₆alk-NH-aryl, the -aryl is -4-chlorophenyl,-3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro-4-chlorophenyl,3-methyl-4-chlorophenyl, 3-fluoro-4-trifluoromethylphenyl,-3-chloro-4-fluorophenyl, -phenyl, -3-(aminomethyl)phenyl,3-(urea)phenyl, 3-methyl-4-chlorophenyl, 3-fluoro-4-chlorophenyl,-3-fluoro-4-trifluoromethylphenyl, difluorophenyl, chlorophenyl,4-chlorophenyl, dichlorophenyl, 3,4-dichlorophenyl, bromophenyl,iodophenyl, chlorofluorophenyl. Thus in some embodiments, R¹ is—CH₂—NH-difluorophenyl, —CH₂—NH-3,4-difluorophenyl,—CH₂—NH-4-chlorophenyl, —CH₂—NH-3-chloro-4-fluorophenyl,—CH₂—NH-4-chloro-3-fluorophenyl, —CH₂—NH-dichlorophenyl,—CH₂—NH-3,4-dichlorophenyl, —CH₂—NH-3-methyl-4-chlorophenyl,—CH₂—NH-3-fluoro-4-trifluoromethylphenyl, —CH₂—NH-3-(aminomethyl)phenyl,—CH₂—NH-3-(urea)phenyl. In some embodiments wherein R¹ is—C₁—C(alk-NH-aryl, the -aryl is 4-chloro-2-(hydroxymethyl)phenyl,-4-chloro-2-(aminomethyl)phenyl,-4-chloro-2-((methylamino)methyl)phenyl, -4-trifluoromethylphenyl,-4-(trifluoromethoxy)phenyl, 4-fluoro-3-trifluoromethylphenyl,-4-isopropylphenyl.

In some aspects, R¹ is —C₁-C₆alk-S-aryl, for example, —C₁alk-S-aryl,—C₂alk-S-aryl, —C₃alk-S-aryl, —C₄alk-S-aryl, —C₅alk-S-aryl,—C₆alk-S-aryl, —CH₂—S-aryl, and the like. In some embodiments wherein R¹is —C₁-C₆alk-S-aryl, the -aryl is -4-chlorophenyl, -3,4-dichlorophenyl,-3,4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3-methyl-4-chlorophenyl,3-fluoro-4-trifluoromethylphenyl, -3-chloro-4-fluorophenyl, -phenyl,-3-(aminomethyl)phenyl, 3-(urea)phenyl, 3-methyl-4-chlorophenyl,3-fluoro-4-chlorophenyl, -3-fluoro-4-trifluoromethylphenyl,difluorophenyl, chlorophenyl, 4-chlorophenyl, dichlorophenyl,3,4-dichlorophenyl, bromophenyl, iodophenyl, chlorofluorophenyl. Thus insome embodiments, R¹ is —CH₂—S-difluorophenyl,—CH₂—S-3,4-difluorophenyl, —CH₂—S-4-chlorophenyl,—CH₂—S-3-chloro-4-fluorophenyl, —CH₂—S-4-chloro-3-fluorophenyl,—CH₂—S-dichlorophenyl, —CH₂—S-3,4-dichlorophenyl,—CH₂—S-3-methyl-4-chlorophenyl, —CH₂—S-3-fluoro-4-trifluoromethylphenyl,—CH₂—S-3-(aminomethyl)phenyl, —CH₂—S-3-(urea)phenyl. In some embodimentswherein R¹ is —C₁-C₆alk-S-aryl, the-aryl-4-chloro-2-(hydroxymethyl)phenyl, -4-chloro-2-(aminomethyl)phenyl,-4-chloro-2-((methylamino)methyl)phenyl, -4-trifluoromethylphenyl,-4-(trifluoromethoxy)phenyl, 4-fluoro-3-trifluoromethylphenyl, or-4-isopropylphenyl.

In some aspects, R¹ is —C₀-C₆alk-heteroaryl, for example,—C₀alk-heteroaryl, —C₁alk-heteroaryl, —C₂alk-heteroaryl,—C₃alk-heteroaryl, —C₄alk-heteroaryl, —C₅alk-heteroaryl, and-C₆alk-heteroaryl. In some embodiments wherein R¹ is—C₀-C₆alk-heteroaryl, the heteroaryl is indolyl, indol-6-yl, indazolyl,indazol-6-yl, quinolinyl, aminoquinolinyl, aminohaloquinolinyl,2-amino-3-bromoquinolin-7-yl, 2-amino-3-chloroquinolin-7-yl,2-amino-3-fluoroquinolin-7-yl,2-((cyclopropylmethyl)amino)quinolin-7-yl, 2-(methylamino)quinolin-7-yl,or 2-aminoquinolin-7-yl. Thus, in some embodiments, R¹ is2-(2-amino-3-bromoquinolin-7-yl)ethyl (i.e.,—CH₂CH₂-(2-amino-3-bromoquinolin-7-yl)),2-(2-amino-3-chloroquinolin-7-yl)ethyl,2-(2-amino-3-fluoroquinolin-7-yl)ethyl,2-(2-((cyclopropylmethyl)amino)quinolin-7-yl)ethyl,2-(2-(methylamino)quinolin-7-yl)ethyl, 2-(2-aminoquinolin-7-yl)ethyl,(indol-6-yl)ethyl, or (indazol-6-yl)ethyl. In some embodiments whereinR¹ is —C₀-C₆alk-heteroaryl, the heteroaryl is3-methylimidazo[1,2-a]pyridin-7-yl, and R¹ is(3-methylimidazo[1,2-a]pyridin-7-yl)ethyl.

In some aspects, R¹ is —C₁-C₆alk-O-heteroaryl, for example,—C₁alk-O-heteroaryl, —C₂alk-O-heteroaryl, —C₃alk-O-heteroaryl,—C₄alk-O-heteroaryl, —C₅alk-O-heteroaryl, and —C₆alk-O-heteroaryl. Insome embodiments wherein R¹ is —C₁-C₆alk-O-heteroaryl, the heteroaryl isindolyl, indol-6-yl, indazolyl, indazol-6-yl, quinolinyl, quinolin-7-yl,aminoquinolinyl, aminohaloquinolinyl, 2-amino-3-bromoquinolin-7-yl,2-amino-3-chloroquinolin-7-yl, 2-amino-3-fluoroquinolin-7-yl,2-((cyclopropylmethyl)amino)quinolin-7-yl, 2-(methylamino)quinolin-7-yl,2-(methoxyamino)quinolin-7-yl, 3-methylimidazo[1,2-a]pyridin-7-yl, or2-aminoquinolin-7-yl. Thus, in some embodiments, R¹ is((2-amino-3-bromoquinolin-7-yl)oxy)methyl (i.e.,—CH₂—O-(2-amino-3-bromoquinolin-7-yl)),((2-amino-3-chloroquinolin-7-yl)oxy)methyl,((2-amino-3-fluoroquinolin-7-yl) oxy)methyl,((2-((cyclopropylmethyl)amino)quinolin-7-yl)oxy)methyl,((2-(methylamino)quinolin-7-yl)oxy)methyl,((2-aminoquinolin-7-yl)oxy)methyl, ((indol-6-yl) oxy)methyl,(2-(methoxyamino)quinolin-7-yl)oxy)methyl, ((quinolin-7-yl)oxy)methyl,((indazol-6-yl)oxy)methyl, or((3-methylimidazo[1,2-a]pyridin-7-yl)oxy)methyl.

In some embodiments wherein R¹ is —C₁-C₆alk-O-heteroaryl, the heteroarylis indolyl, indol-6-yl, indazolyl, indazol-6-yl, quinolinyl,quinolin-7-yl, aminoquinolinyl, aminohaloquinolinyl,2-amino-3-bromoquinolin-7-yl, 2-amino-3-chloroquinolin-7-yl,2-amino-3-fluoroquinolin-7-yl,2-((cyclopropylmethyl)amino)quinolin-7-yl, 2-(methylamino)quinolin-7-yl,2-(methoxyamino)quinolin-7-yl, or 2-aminoquinolin-7-yl. Thus, in someembodiments, R¹ is ((2-amino-3-bromoquinolin-7-yl)oxy)methyl (i.e.,—CH₂—O-(2-amino-3-bromoquinolin-7-yl)),((2-amino-3-chloroquinolin-7-yl)oxy)methyl,((2-amino-3-fluoroquinolin-7-yl) oxy)methyl,((2-((cyclopropylmethyl)amino)quinolin-7-yl)oxy)methyl,((2-(methylamino)quinolin-7-yl)oxy)methyl,((2-aminoquinolin-7-yl)oxy)methyl, ((indol-6-yl) oxy)methyl,2-(methoxyamino)quinolin-7-yl)oxy)methyl, ((quinolin-7-yl)oxy)methyl or((indazol-6-yl)oxy)methyl.

In other embodiments wherein R¹ is —C₁-C₆alk-O-heteroaryl, theheteroaryl is indolyl, indol-6-yl, indazolyl, indazol-6-yl, quinolinyl,aminoquinolinyl, aminohaloquinolinyl, 2-amino-3-bromoquinolin-7-yl,2-amino-3-chloroquinolin-7-yl, 2-amino-3-fluoroquinolin-7-yl,2-((cyclopropylmethyl)amino)quinolin-7-yl, 2-(methylamino)quinolin-7-yl,or 2-aminoquinolin-7-yl. Thus, in some embodiments, R¹ is((2-amino-3-bromoquinolin-7-yl)oxy)methyl (i.e.,—CH₂—O-(2-amino-3-bromoquinolin-7-yl)),((2-amino-3-chloroquinolin-7-yl)oxy)methyl,((2-amino-3-fluoroquinolin-7-yl) oxy)methyl,((2-((cyclopropylmethyl)amino)quinolin-7-yl)oxy)methyl,((2-(methylamino)quinolin-7-yl)oxy)methyl,((2-aminoquinolin-7-yl)oxy)methyl, ((indol-6-yl) oxy)methyl, or((indazol-6-yl)oxy)methyl.

In some aspects, R¹ is —C₁-C₆alk-S-heteroaryl, for example,—C₁alk-S-heteroaryl, —C₂alk-S-heteroaryl, —C₃alk-S-heteroaryl,—C₄alk-S-heteroaryl, —C₅alk-S-heteroaryl, and -C₆alk-S-heteroaryl. Insome embodiments wherein R¹ is —C₁-C₆alk-S-heteroaryl, the heteroaryl isindolyl, indol-6-yl, indazolyl, indazol-6-yl, quinolinyl,aminoquinolinyl, aminohaloquinolinyl, 2-amino-3-bromoquinolin-7-yl,2-amino-3-chloroquinolin-7-yl, 2-amino-3-fluoroquinolin-7-yl,2-((cyclopropylmethyl)amino)quinolin-7-yl, 2-(methylamino)quinolin-7-yl,or 2-aminoquinolin-7-yl. Thus, in some embodiments, R¹ is((2-amino-3-bromoquinolin-7-yl)thio)methyl (i.e.,—CH₂—S-(2-amino-3-bromoquinolin-7-yl)),((2-amino-3-chloroquinolin-7-yl)thio)methyl,((2-amino-3-fluoroquinolin-7-yl)thio)methyl,((2-((cyclopropylmethyl)amino)quinolin-7-yl)thio)methyl,((2-(methylamino)quinolin-7-yl)thio)methyl,((2-aminoquinolin-7-yl)thio)methyl, ((indol-6-yl) thio)methyl, or((indazol-6-yl)thio)methyl. In some embodiments wherein R¹ is—C₁-C₆alk-S-heteroaryl, the heteroaryl is3-methylimidazo[1,2-a]pyridin-7-yl, and R¹ is((3-methylimidazo[1,2-a]pyridin-7-yl)thio)methyl.

In some aspects, R¹ is —C₁-C₆alk-NH-heteroaryl, for example,—C₁alk-NH-heteroaryl, —C₂alk-NH-heteroaryl, —C₃alk-NH-heteroaryl,—C₄alk-NH-heteroaryl, —C₅alk-NH-heteroaryl, and -C₆alk-NH-heteroaryl. Insome embodiments wherein R¹ is -C₁-C₆alk-NH-heteroaryl, the heteroarylis indolyl, indol-6-yl, indazolyl, indazol-6-yl, quinolinyl,aminoquinolinyl, aminohaloquinolinyl, 2-amino-3-bromoquinolin-7-yl,2-amino-3-chloroquinolin-7-yl, 2-amino-3-fluoroquinolin-7-yl,2-((cyclopropylmethyl)amino)quinolin-7-yl, 2-(methylamino)quinolin-7-yl,or 2-aminoquinolin-7-yl. Thus, in some embodiments, R¹ is((2-amino-3-bromoquinolin-7-yl)amino)methyl (i.e.,—CH₂—NH-(2-amino-3-bromoquinolin-7-yl)),((2-amino-3-chloroquinolin-7-yl)amino)methyl,((2-amino-3-fluoroquinolin-7-yl)amino)methyl,((2-((cyclopropylmethyl)amino)quinolin-7-yl)amino)methyl,((2-(methylamino)quinolin-7-yl)amino)methyl,((2-aminoquinolin-7-yl)amino)methyl, ((indol-6-yl) amino)methyl, or((indazol-6-yl)amino)methyl. In some embodiments wherein R¹ is—C₁-C₆alk-NH-heteroaryl, the heteroaryl is3-methylimidazo[1,2-a]pyridin-7-yl. Thus, in some embodiments. R¹ is((3-methylimidazo[1,2-a]pyridin-7-yl)amino)methyl.

In some aspects, R¹ is —C(O)—NH-aryl. In some embodiments wherein R¹ is—C(O)—NH-aryl, the -aryl is -4-chlorophenyl, -3,4-dichlorophenyl,-3,4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3-methyl-4-chlorophenyl,3-fluoro-4-trifluoromethylphenyl, or -3-chloro-4-fluorophenyl, -phenyl,-3-(aminomethyl)phenyl, 3-(urea)phenyl, 3-methyl-4-chlorophenyl,3-fluoro-4-chlorophenyl, -3-fluoro-4-trifluoromethylphenyl,difluorophenyl, chlorophenyl, 4-chlorophenyl, dichlorophenyl,3,4-dichlorophenyl, bromophenyl, iodophenyl, chlorofluorophenyl, orbenzo[d][1,3]dioxazole. In some embodiments wherein R¹ is —C(O)—NH-aryl,the -aryl is -4-chloro-2-(hydroxymethyl)phenyl,-4-chloro-2-(aminomethyl)phenyl,-4-chloro-2-((methylamino)methyl)phenyl, -4-trifluoromethylphenyl,4-fluoro-3-trifluoromethylphenyl, -4-isopropylphenyl, or-4-(trifluoromethoxy)phenyl.

In some aspects, R¹ is —C₁-C₆alk-S(O)aryl, for example, —C₁alk-S(O)aryl,—C₂alk-S(O)aryl, —C₃alk-S(O)aryl, —C₄alk-S(O)aryl, —C₅alk-S(O)aryl, and-C₆alk-S(O)aryl, wherein aryl is phenyl, naphthyl, fluorophenyl,difluorophenyl, fluoronaphthyl, chlorophenyl, bromophenyl, iodophenyl,methylphenyl, and the like.

In some aspects, R¹ is —C₁-C₆alk-S(O)₂aryl, for example,—C₁alk-S(O)₂aryl, —C₂alk-S(O)₂aryl, —C₃alk-S(O)₂aryl, —C₄alk-S(O)₂aryl,—C₅alk-S(O)₂aryl, and -C₆alk-S(O)₂aryl, wherein aryl is phenyl,naphthyl, fluorophenyl, difluorophenyl, fluoronaphthyl, chlorophenyl,bromophenyl, iodophenyl, methylphenyl, and the like.

In some aspects, R¹ is —C₁-C₆alk-S(O)heteroaryl, for example,—C₁alk-S(O)heteroaryl, —C₂alk-S(O)heteroaryl, —C₃alk-S(O)heteroaryl,—C₄alk-S(O)heteroaryl, —C₅alk-S(O) heteroaryl, and-C₆alk-S(O)heteroaryl, wherein heteroaryl is indolyl, indol-6-yl,indazolyl, indazol-6-yl, quinolinyl, aminoquinolinyl,aminohaloquinolinyl, 2-amino-3-bromoquinolin-7-yl,2-amino-3-chloroquinolin-7-yl, 2-amino-3-fluoroquinolin-7-yl,2-((cyclopropylmethyl)amino)quinolin-7-yl, 2-(methylamino)quinolin-7-yl,or 2-aminoquinolin-7-yl.

In some aspects, R¹ is —C₁-C₆alk-S(O)₂heteroaryl, for example,—C₁alk-S(O)₂heteroaryl, —C₂alk-S(O)₂heteroaryl, —C₃alk-S(O)₂heteroaryl,—C₄alk-S(O)₂heteroaryl, —C₅alk-S(O)₂heteroaryl, and-C₆alk-S(O)₂heteroaryl, wherein heteroaryl is indolyl, indol-6-yl,indazolyl, indazol-6-yl, quinolinyl, aminoquinolinyl,aminohaloquinolinyl, 2-amino-3-bromoquinolin-7-yl,2-amino-3-chloroquinolin-7-yl, 2-amino-3-fluoroquinolin-7-yl,2-((cyclopropylmethyl)amino)quinolin-7-yl, 2-(methylamino)quinolin-7-yl,or 2-aminoquinolin-7-yl.

In compounds of the present disclosure, R² is —C₁-C₆alkyl,—C₁-C₆haloalkyl, —C₂-C₆alkenyl, or —C₂-C₆alkynyl.

In some embodiments, R² is —C₁-C₆alkyl, —C₂-C₆alkenyl, or —C₂-C₆alkynyl.

In some aspects, R² is —C₁-C₆alkyl, for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. Insome embodiments, R² is methyl.

In other aspects, R² is —C₁-C₆haloalkyl, for example, —CF₃ or —CHF2. Insome embodiments, R² is —CF₃.

In some aspects, R² is —C₂-C₆alkenyl, preferably —C₂-C₄alkenyl, forexample, vinyl, allyl, and the like.

In other aspects, R² is —C₂-C₆alkynyl, preferably —C₂-C₄alkynyl, forexample, ethynyl, propargyl, and the like.

In compounds of the present disclosure, R³ is H, halo, —C₁-C₆alkyl, orNH₂. Thus in some embodiments, R³ is H. In other embodiments, R³ ishalo, for example F, Cl, Br, or I. In other embodiments, R³ is—C₁-C₆alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, s-butyl, t-butyl, pentyl, and the like. Thus, in someembodiments, R³ is methyl (Me). In yet other embodiments, R³ is NH₂. Inthe most preferred embodiments, R³ is H.

In compounds of the present disclosure, R⁴ is H, halo, —C₁-C₆alkyl,—C₁-C₆alk-O—C₁-C₆alkyl, —NR⁶R^(6′), —NHCONR⁶R^(6′), NHC(S)NR⁶R^(6′),—NH—O—R⁶, or —NH—NR⁶R^(6′). In some embodiments, R⁴ is halo,—C₁-C₆alkyl, —C₁-C₆alk-O—C₁-C₆alkyl, —NR⁶R^(6′), —NHCONR⁶R^(6′),NHC(S)NR⁶R^(6′), —NH—O—R⁶, or —NH—NR⁶R^(6′).

In some aspects, R⁴ is H.

In some aspects, R⁴ is halo, for example chloro, fluoro, bromo, or iodo.In some embodiments, R⁴ is chloro.

In some aspects, R⁴ is —C₁-C₆alkyl, for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. Insome embodiments, R⁴ is methyl.

In some aspects, R⁴ is —C₁-C₆alk-O—C₁-C₆alkyl, for example,—C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₄alk-O—C₁-C₆alkyl,—C₁-C₃alk-O—C₁-C₆alkyl, —C₁-C₂alk-O—C₁-C₆alkyl, —C₁alk-O—C₁-C₆alkyl,—C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₆alk-O—C₁-C₄alkyl, —C₁-C₆alk-O—C₁-C₃alkyl,—C₁-C₆alk-O—C₁-C₂alkyl, or —C₁-C₆alk-O—C₁alkyl. In some embodiments, R⁴is —CH₂CH₂—O—CH₃.

In some aspects, R⁴ is —NR⁶R^(6′). Thus, in some embodiments wherein R⁶and R^(6′) are both H, R⁴ is —NH₂. In some embodiments wherein R⁶ andR^(6′) are both methyl, R⁴ is —N(CH₃)₂. In embodiments wherein R⁶ is Hand R^(6′) is methyl, R⁴ is —NH(CH₃).

In some aspects, R⁴ is —NHCONR⁶R^(6′). Thus, in some embodiments whereinR⁶ and R^(6′) are both H, R⁴ is —NHCONH₂. In embodiments wherein R⁶ andR^(6′) are both methyl, R⁴ is —NHCON(CH₃)₂. In embodiments wherein R⁶ isH and R^(6′) is methyl, R⁴ is —NHCONHCH₃.

In some aspects, R⁴ is NHC(S)NR⁶R^(6′). Thus, in some embodimentswherein R⁶ and R^(6′) are both H, R⁴ is —NHC(S)NH₂. In embodimentswherein R⁶ and R^(6′) are both methyl, R⁴ is —NHC(S)N(CH₃)₂. Inembodiments wherein R⁶ is H and R^(6′) is methyl, R⁴ is —NHC(S)NHCH₃.

In some aspects, R⁴ is —NH—O—R⁶. In some embodiments wherein R⁶ isC₁-C₆alkyl, for example, methyl, R⁴ is —NH—OCH₃. In some embodimentswherein R⁶ is ethyl, R⁴ is —NH—OCH₂CH₃. In some embodiments wherein R⁶is H, R⁴ is —NH—OH.

In some aspects, R⁴ is —NH—NR⁶R^(6′). In some embodiments wherein R⁶ andR^(6′) are both H, R⁴ is —NH—NH₂. In embodiments wherein R⁶ and R^(6′)are both C₁-C₆alkyl, for example, methyl, R⁴ is —NH—N(CH₃)₂. Inembodiments wherein R⁶ is H and R^(6′) is C₁-C₆alkyl, for example,methyl, R⁴ is —NH—NHCH₃.

It will be apparent that when R⁴ is —NH—O—R⁶ or —NH—NR⁶R^(6′), thecompounds of Formula I may exist as tautomers having (E)- or(Z)-geometry at the exocyclic carbon-nitrogen double bond. The compoundsof Formula I described and claimed herein are meant to encompass allsuch tautomers and geometric isomers. The depiction of a particulartautomer or geometric isomer is not intended to be limiting. Forexample, when R⁴ is —NH—O—R⁶, compounds of Formula I may be representedby any of the following equivalent structures:

Similarly, when R⁴ is —NH—NR⁶R^(6′), compounds of Formula I may berepresented by any of the following equivalent structures:

In compounds of the present disclosure, R⁵ is H, halo, —C₁-C₆alkyl,—C₁-C₆haloalkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, or —C₁-C₆alk-OH. In someaspects, R⁵ is H.

In other aspects, R⁵ is halo, for example, fluoro, chloro, bromo, oriodo. In some embodiments, R⁵ is fluoro.

In some aspects, R⁵ is —C₁-C₆alkyl, for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. Inother aspects, R⁵ is —C₂-C₆alkenyl, preferably —C₂-C₄alkenyl, forexample, vinyl, allyl, and the like. In yet other aspects, R¹ is—C₂-C₆alkynyl, preferably —C₂-C₄alkynyl, for example, ethynyl,propargyl, and the like.

In other aspects, R⁵ is —C₁-C₆haloalkyl, for example, —CF₃ or —CHF₂. Insome embodiments, R⁵ is —CF₃.

In some aspects, R⁵ is —C₁-C₆alk-OH, for example, —C₁-C₆alk-OH,—C₁-C₅alk-OH, —C₁-C₄alk-OH, —C₁-C₃alk-OH, —C₁-C₂alk-OH, or —C₁alk-OH. Insome embodiments. R⁵ is —CH₂OH.

In compounds of the present disclosure, R⁶ and R^(6′) are eachindependently H, C₁-C₆alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like), or—C₁-C₆alk-OC₁-C₆alkyl (e.g., C₁-C₆alk-OC₁-C₆alkyl, C₁-C₆alk-OC₁-C₆alkyl,C₁-C₄alk-OC₁-C₆alkyl, C₁-C₃alk-OC₁-C₆alkyl, C₁-C₂alk-OC₁-C₆alkyl,C₁alk-OC₁-C₆alkyl, C₁-C₆alk-OC₁-C₅alkyl, C₁-C₆alk-OC₁-C₄alkyl,C₁-C₆alk-OC₁-C₃alkyl, C₁-C₆alk-OC₁-C₂alkyl, or C₁-C₆alk-OC₁alkyl).

In some embodiments, R⁶ is H or C₁-C₆alkyl. In some embodiments, R^(6′)is H or C₁-C₆alkyl.

In some embodiments, R⁶ and R^(6′) are each H.

In other embodiments, R⁶ and R^(6′) are each independently C₁-C₆alkyl.Thus, in some embodiments R⁶ is methyl and R^(6′) is methyl.

In some aspects, R⁶ is C₁-C₆alkyl and R^(6′) is H. Thus, in someembodiments, R⁶ is methyl and R^(6′) is H.

In other aspects, R⁶ and R^(6′) are each independently—C₁-C₆alk-OC₁-C₆alkyl.

In other aspects, R⁶ is —C₁-C₆alk-OC₁-C₆alkyl and R^(6′) is H.

In some embodiments of the disclosure, R⁶ and R^(6′), together with theatom to which they are attached, form a C₂-C₆heterocycloalkyl ring, forexample, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl,oxazepanyl, piperazinyl, and the like. In some preferred embodiments, R⁶and R^(6′), together with the atom to which they are attached, form aC₃-C₆heterocycloalkyl ring, for example, azepanyl, azetidinyl,pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl,morpholinyl, thiomorpholinyl, oxazepanyl, piperazinyl, and the like.

Preferred embodiments are those wherein R¹ is —CH₂—O—CH₃, —CH₂—S—CH₃,—CH₂—S—CH₂CH₂CH(NH₂)—CO₂H, —CH(OH)-4-chlorophenyl,—CH(OH)-3,4-dichlorophenyl, —CH(OH)-3,4-difluorophenyl,—CH(OH)-3-fluoro-4-chlorophenyl, —CH(OH)-3-chloro-4-fluorophenyl,—CH(OH)-3-methyl-4-chlorophenyl,—CH(OH)-3-fluoro-4-trifluoromethylphenyl, —CH(F)-4-chlorophenyl,—CH(F)-3,4-dichlorophenyl, —CH(F)-3,4-difluorophenyl,—CH(F)-3-fluoro-4-chlorophenyl, —CH(F)-3-chloro-4-fluorophenyl,—CH(F)-3-methyl-4-chlorophenyl, —CH(F)-3-fluoro-4-trifluoromethylphenyl,—C(Me)(OH)-4-chlorophenyl, —C(Me)(OH)-3,4-dichlorophenyl,—C(Me)(OH)-3,4-difluorophenyl, —C(Me)(OH)-3-fluoro-4-chlorophenyl,—C(Me)(OH)-3-chloro-4-fluorophenyl, —C(Me)(OH)-3-methyl-4-chlorophenyl,—C(Me)(OH)-3-fluoro-4-trifluoromethylphenyl, —CH₂—O-phenyl,—CH₂—O-difluorophenyl, —CH₂—O-3,4-difluorophenyl, —CH₂—O-4-chlorophenyl,—CH₂—O-3-chloro-4-fluorophenyl, —CH₂—O-4-chloro-3-fluorophenyl,—CH₂—O-dichlorophenyl, —CH₂—O-3,4-dichlorophenyl,—CH₂—O-3-methyl-4-chlorophenyl, —CH₂—O-3-fluoro-4-trifluoromethylphenyl,—CH₂—O-3-(aminomethyl)phenyl, —CH₂—O-3-(urea)phenyl,((2-amino-3-bromoquinolin-7-yl)oxy)methyl (i.e.,—CH₂—O-(2-amino-3-bromoquinolin-7-yl)),((2-amino-3-chloroquinolin-7-yl)oxy)methyl,((2-amino-3-fluoroquinolin-7-yl) oxy)methyl,((2-(methylamino)quinolin-7-yl)oxy)methyl,((2-aminoquinolin-7-yl)oxy)methyl, ((indol-6-yl)oxy)methyl,((indazol-6-yl)oxy)methyl, 2-(2-aminoquinolin-7-yl)ethyl,((2-aminoquinolin-7-yl)thio)methyl, ((2-aminoquinolin-7-yl)amino)methyl.Other preferred embodiments are those wherein R¹ is((3-methylimidazo[1,2-a]pyridin-7-yl)oxy)methyl (i.e.,—CH₂—O-3-methylimidazo[1,2-a]pyridin-7-yl), —CH(OH)-4-isopropylphenyl,—CH(OH)-4-trifluoromethylphenyl, —CH(OH)-4-(trifluoromethoxy)phenyl,—CH(OH)-4-fluoro-3-trifluoromethylphenyl,—CH₂-(4-chloro-2-(hydroxymethyl)phenyl),—CH₂-(4-chloro-2-(aminomethyl)phenyl), or—CH₂-(4-chloro-2-((methylamino)methyl)phenyl).

Preferred embodiments are those in which R² is methyl.

In some aspects, the present disclosure is directed to compounds ofFormula I-A

wherein R¹ is —C₀-C₆alk-C₁-C₆alkyl, —C₀-C₆alk-C₁-C₆haloalkyl,—C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₆alk-S—C₁-C₆alkyl,—C₁-C₆alk-S—C₁-C₆alk-CO₂H, —C₁-C₆alk-aryl, —C₁-C₆alk-O-aryl,—C₀-C₆alk-heteroaryl, —C₁-C₆alk-O-heteroaryl, —C₁-C₆alk-S-heteroaryl, or—C₁-C₆alk-NH-heteroaryl; R² is methyl, trifluoromethyl, ethynyl, orvinyl; R⁴ is halo, C₁-C₆alkyl, —NHC(O)NR⁶R^(6′), —NR⁶R^(6′), —NH—O—R⁶ or—NH—NR⁶R^(6′); R⁵ is H or F; and R⁶ and R^(6′) are each independently Hor —C₁-C₆alkyl.

In some embodiments, the compounds of formula I-A are those in which R¹is —C₀-C₆alk-C₁-C₆alkyl, —C₀-C₆alk-C₁-C₆haloalkyl,—C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₆alk-S—C₁-C₆alkyl,—C₁-C₆alk-S—C₁-C₆alk-CO₂H, —C₁-C₆alk-aryl, —C₁-C₆alk-O-aryl,—C₀-C₆alk-heteroaryl, —C₁-C₆alk-O-heteroaryl, —C₁-C₆alk-S-heteroaryl, or—C₁-C₆alk-NH-heteroaryl; R² is methyl, ethynyl, or vinyl; R⁴ is halo,C₁-C₆alkyl, —NHC(O)NR⁶R^(6′), —NR⁶R^(6′), —NH—O—R⁶ or —NH—NR⁶R^(6′); R⁵is H or F; and R⁶ and R^(6′) are each independently H or —C₁-C₆alkyl.

In some embodiments, the compounds of formula I-A are those in which R¹is —C₁-C₆alk-aryl or —C₁-C₆alk-O-heteroaryl; —R² is methyl, ethynyl, orvinyl; R⁴ is halo, C₁-C₆alkyl, —NHC(O)NR⁶R^(6′), —NR⁶R^(6′), —NH—O—R⁶ or—NH—NR⁶R^(6′); R⁵ is H or F; and R⁶ and R^(6′) are each independently Hor —C₁-C₆alkyl.

In some embodiments, the compounds of formula I-A are those in which R¹is —C₁-C₆alk-O-heteroaryl; R² is methyl, ethynyl, or vinyl; R⁴ is halo,C₁-C₆alkyl, —NHC(O)NR⁶R^(6′), —NR⁶R^(6′), —NH—O—R⁶ or —NH—NR⁶R^(6′); R⁵is H or F; and R⁶ and R^(6′) are each independently H or —C₁-C₆alkyl.

In some embodiments, the compounds of formula I-A are those in which R¹is —C₁-C₆alk-aryl; R² is methyl, ethynyl, or vinyl; R⁴ is halo,C₁-C₆alkyl, —NHC(O)NR⁶R^(6′), —NR⁶R^(6′), —NH—O—R⁶ or —NH—NR⁶R^(6′); R¹is H or F; and R⁶ and R^(6′) are each independently H or —C₁-C₆alkyl.

In some embodiments, the compounds of formula I-A are those in which R¹is —C₁-C₆alk-aryl wherein the aryl is a mono- or bicyclic-aromatichydrocarbon ring structure having 6 or 10 carbon atoms in the ring,wherein one or more of the carbon atoms in the ring is optionallysubstituted with a halogen atom, a —C₁-C₃ alkyl group, anamino-substituted —C₁-C₃ alkyl group, a C₁-C₃haloalkyl group, an aminogroup (i.e., —NH₂), or a substituted amino group; —R² is methyl,ethynyl, or vinyl; R⁴ is halo, C₁-C₆alkyl, —NHC(O)NR⁶R^(6′), —NR⁶R^(6′),—NH—O—R⁶ or —NH—NR⁶R^(6′); R⁵ is H or F; and R⁶ and R^(6′) are eachindependently H or —C₁-C₆alkyl.

In some aspects, the present disclosure is directed to compounds ofFormula I-B

wherein R¹ is —C₀-C₆alk-heteroaryl, —C₁-C₆alk-O-heteroaryl,—C₁-C₆alk-S-heteroaryl, or —C₁-C₆alk-NH-heteroaryl; R⁴ is —NR⁶R^(6′),—NH—O—R⁶ or —NH—NR⁶R^(6′); R¹ is H or F; and R⁶ and R^(6′) are eachindependently H or —C₁-C₆alkyl. In some preferred embodiments, thecompounds of Formula I-B are those wherein R¹ is —C₁-C₆alk-O-heteroaryl;R⁴ is —NR⁶R^(6′), —NH—O—R⁶ or —NH—NR⁶R^(6′); R⁵ is H or F; and R⁶ andR^(6′) are each independently H or —C₁-C₆alkyl.

In some preferred embodiments, the compounds of Formula I-B are thosewherein R¹ is ((2-amino-3-bromoquinolin-7-yl)oxy)methyl (i.e.,—CH₂—O-(2-amino-3-bromoquinolin-7-yl)),((2-amino-3-chloroquinolin-7-yl)oxy)methyl,((2-amino-3-fluoroquinolin-7-yl) oxy)methyl,((2-(methylamino)quinolin-7-yl)oxy)methyl,((2-aminoquinolin-7-yl)oxy)methyl, ((indol-6-yl) oxy)methyl,((indazol-6-yl)oxy)methyl, 2-(2-aminoquinolin-7-yl)ethyl,((2-aminoquinolin-7-yl)thio)methyl, or((2-aminoquinolin-7-yl)amino)methyl; R⁴ is —NH₂, —NH—O—CH₃ or —NH—NHCH₃;and R⁵ is H or F.

In some preferred embodiments, the compounds of Formula I-B are thosewherein R¹ is ((quinolin-7-yl)oxy)methyl,((2-amino-3-bromoquinolin-7-yl)oxy)methyl (i.e.,—CH₂—O-(2-amino-3-bromoquinolin-7-yl)),((2-amino-3-chloroquinolin-7-yl)oxy)methyl,((2-amino-3-fluoroquinolin-7-yl) oxy)methyl,((2-(methylamino)quinolin-7-yl)oxy)methyl,((2-(methoxyamino)quinolin-7-yl)oxy)methyl,((2-aminoquinolin-7-yl)oxy)methyl, ((indol-6-yl) oxy)methyl,((indazol-6-yl)oxy)methyl, 2-(2-aminoquinolin-7-yl)ethyl,((2-aminoquinolin-7-yl)thio)methyl,((3-methylimidazo[1,2-a]pyridine-7yl)oxy)methyl, or((2-aminoquinolin-7-yl)amino)methyl; R⁴ is —NH₂, —NH—OH, —NH—O—CH₃ or—NH—NHCH₃; and R⁵ is H or F.

In some preferred embodiments, the compounds of Formula I-B are thosewherein R¹ is ((quinolin-7-yl)oxy)methyl,((2-amino-3-bromoquinolin-7-yl)oxy)methyl (i.e.,—CH₂—O-(2-amino-3-bromoquinolin-7-yl)),((2-amino-3-chloroquinolin-7-yl)oxy)methyl,((2-amino-3-fluoroquinolin-7-yl)oxy)methyl,((2-(methylamino)quinolin-7-yl)oxy)methyl,((2-(methoxyamino)quinolin-7-yl)oxy)methyl,((2-aminoquinolin-7-yl)oxy)methyl, ((indol-6-yl) oxy)methyl,((indazol-6-yl)oxy)methyl, 2-(2-aminoquinolin-7-yl)ethyl,((2-aminoquinolin-7-yl)thio)methyl,((3-methylimidazo[1,2-a]pyridine-7yl)oxy)methyl, or((2-aminoquinolin-7-yl)amino)methyl; R⁴ is —NR⁶R^(6′), —NH—O—R⁶ or—NH—NR⁶R^(6′); R⁵ is H or F; and R⁶ and R^(6′) are each independently Hor —C₁-C₆alkyl.

In some aspects, the present disclosure is directed to compounds ofFormula I-B wherein R¹ is —C₁-C₆alk-aryl, R⁴ is —NR⁶R^(6′), —NH—O—R⁶ or—NH—NR⁶R^(6′); R⁵ is H or F; and R⁶ and R^(6′) are each independently Hor —C₁-C₆alkyl.

In some embodiments, the compounds of Formula I-B are those wherein R¹is —C₁-C₆alk-aryl wherein the aryl is a mono- or bicyclic-aromatichydrocarbon ring structure having 6 or 10 carbon atoms in the ring,wherein one or more of the carbon atoms in the ring is optionallysubstituted with a halogen atom, a —C₁-C₃ alkyl group, anamino-substituted —C₁-C₃ alkyl group, a C₁-C₃haloalkyl group, an aminogroup (i.e., —NH₂), or a substituted amino group; R⁴ is —NR⁶R^(6′),—NH—O—R⁶ or —NH—NR⁶R^(6′); R⁵ is H or F; and R⁶ and R^(6′) are eachindependently H or —C₁-C₆alkyl.

In some preferred embodiments, the compounds of Formula I-B are thosewherein R¹ is -C₁alk-aryl, and R⁴ is —NR⁶R^(6′), —NH—O—R⁶ or—NH—NR⁶R^(6′); R⁵ is H or F; and R⁶ and R^(6′) are each independently Hor —C₁-C₆alkyl.

In other preferred embodiments, the compounds of Formula I-B are thosewherein R¹ is -C₁alk-aryl, R⁴ is —NH₂, —NH—O—CH₃ or —NH—NHCH₃; and R⁵ isH or F.

In other preferred embodiments, the compounds of Formula I-B are thosewherein R¹ is —CH(OH)-4-chlorophenyl.—CH(OH)-4-chloro-2-(hydroxymethyl)phenyl, —CH(OH)-3,4-dichlorophenyl,—CH(OH)-3,4-difluorophenyl, —CH(OH)-3-fluoro-4-chlorophenyl,—CH(OH)-3-methyl-4-chlorophenyl,—CH(OH)-3-fluoro-4-trifluoromethylphenyl,—CH(OH)-4-trifluoromethylphenyl, —CH(OH)-4-(trifluoromethoxy)phenyl,—CH(OH)-4-fluoro-3-trifluoromethylphenyl,—CH(OH)-benzo[d][1,3]dioxazole, —CH(OH)-4-isopropylphenyl, or—CH(OH)-3-chloro-4-fluorophenyl; R⁴ is —NR⁶R^(6′), —NH—O—R⁶ or—NH—NR⁶R^(6′); R⁵ is H or F; and R⁶ and R^(6′) are each independently Hor —C₁-C₆alkyl.

In other preferred embodiments, the compounds of Formula I-B are thosewherein R¹ is —CH(OH)-4-chlorophenyl,—CH(OH)-4-chloro-2-(hydroxymethyl)phenyl, —CH(OH)-3,4-dichlorophenyl,—CH(OH)-3,4-difluorophenyl, —CH(OH)-3-fluoro-4-chlorophenyl,—CH(OH)-3-methyl-4-chlorophenyl,—CH(OH)-3-fluoro-4-trifluoromethylphenyl,—CH(OH)-4-trifluoromethylphenyl, —CH(OH)-4-(trifluoromethoxy)phenyl,—CH(OH)-4-fluoro-3-trifluoromethylphenyl,—CH(OH)-benzo[d][1,3]dioxazole, —CH(OH)-4-isopropylphenyl, or—CH(OH)-3-chloro-4-fluorophenyl; R⁴ is —NH₂, —NH—O—CH₃ or —NH—NHCH₃; andR⁵ is H or F.

In other preferred embodiments, the compounds of Formula I-B are thosewherein R¹ is —CH₂-4-chloro-2-(hydroxymethyl)phenyl,—CH₂-4-chloro-2-(aminomethyl)phenyl,—CH₂-(4-chloro-2-(methylamino)methyl)phenyl, —CH₂-3,4-dichlorophenyl,—CH₂-benzo[d][1,3]dioxazole; R⁴ is H, —NR⁶R^(6′), —NH—O—R⁶ or—NH—NR⁶R^(6′); R⁵ is H or F; and R⁶ and R^(6′) are each independently Hor —C₁-C₆alkyl.

In other preferred embodiments, the compounds of Formula I-B are thosewherein R¹ is —CH₂-4-chloro-2-(hydroxymethyl)phenyl,—CH₂-4-chloro-2-(aminomethyl)phenyl,—CH₂-(4-chloro-2-(methylamino)methyl)phenyl, —CH₂-3,4-dichlorophenyl,—CH₂-benzo[d][1,3]dioxazole; R⁴ is H, —NH₂, —NH—OH, —NH—O—CH₃ or—NH—NHCH₃; and R⁵ is H or F.

In other preferred embodiments, the compounds of Formula I-B are thosewherein R¹ is —CH(OH)-4-chlorophenyl, —CH(OH)-3,4-dichlorophenyl,—CH(OH)-3,4-difluorophenyl, —CH(OH)-3-fluoro-4-chlorophenyl,—CH(OH)-3-chloro-4-fluorophenyl, —CH(OH)-3-methyl-4-chlorophenyl,—CH(OH)-3-fluoro-4-trifluoromethylphenyl, —C(Me)(OH)-4-chlorophenyl,—C(Me)(OH)-3,4-dichlorophenyl, —C(Me)(OH)-3,4-difluorophenyl,—C(Me)(OH)-3-fluoro-4-chlorophenyl, —C(Me)(OH)-3-chloro-4-fluorophenyl,—C(Me)(OH)-3-methyl-4-chlorophenyl, or—C(Me)(OH)-3-fluoro-4-trifluoromethylphenyl; R⁴ is —NR⁶R^(6′), —NH—O—R⁶or —NH—NR⁶R^(6′); R⁵ is H or F; and R⁶ and R^(6′) are each independentlyH or —C₁-C₆alkyl.

In yet other preferred embodiments, the compounds of Formula I-B arethose wherein R¹ is —CH(OH)-4-chlorophenyl, —CH(OH)-3,4-dichlorophenyl,—CH(OH)-3,4-difluorophenyl, —CH(OH)-3-fluoro-4-chlorophenyl,—CH(OH)-3-chloro-4-fluorophenyl, —CH(OH)-3-methyl-4-chlorophenyl,—CH(OH)-3-fluoro-4-trifluoromethylphenyl, —C(Me)(OH)-4-chlorophenyl,—C(Me)(OH)-3,4-dichlorophenyl, —C(Me)(OH)-3,4-difluorophenyl,—C(Me)(OH)-3-fluoro-4-chlorophenyl, —C(Me)(OH)-3-chloro-4-fluorophenyl,—C(Me)(OH)-3-methyl-4-chlorophenyl, or—C(Me)(OH)-3-fluoro-4-trifluoromethylphenyl; R⁴ is —NH₂, —NH—O—CH₃ or—NH—NHCH₃; and R⁵ is H or F.

In yet other preferred embodiments, the compounds of Formula I-B arethose wherein R¹ is —CH(OH)-4-chlorophenyl, —CH(OH)-3,4-dichlorophenyl,or —CH(OH)-3-methyl-4-chlorophenyl; R⁴ is —NH₂, —NH—O—CH₃ or —NH—NHCH₃;and R¹ is H or F. In yet other preferred embodiments, the compounds ofFormula I-B are those wherein R¹ is —CH(OH)-4-chlorophenyl,—CH(OH)-3,4-dichlorophenyl, or —CH(OH)-3-methyl-4-chlorophenyl; R⁴ is—NH₂, —NH—OH, —NH—O—CH₃ or —NH—NHCH₃; and R⁵ is H or F.

In some aspects, the present disclosure is directed to compounds ofFormula I-B wherein R¹ is —C₁-C₆alk-aryl, R⁴ is —C₁-C₆alkyl; and R⁵ is Hor F. Some preferred embodiments are those in which R¹ is -C₁alk-aryl,and R⁴ is —CH₃; and R⁵ is H or F.

In some aspects, the present disclosure is directed to compounds ofFormula I-B wherein R¹ is —C₁-C₆alk-aryl wherein the aryl is a mono- orbicyclic-aromatic hydrocarbon ring structure having 6 or 10 carbon atomsin the ring, wherein one or more of the carbon atoms in the ring isoptionally substituted with a halogen atom, a —C₁-C₃ alkyl group, anamino-substituted —C₁-C₃ alkyl group, a C₁-C₃haloalkyl group, an aminogroup (i.e., —NH₂), or a substituted amino group; R⁴ is —C₁-C₆alkyl; andR¹ is H or F.

In preferred embodiments, the compounds of Formula I-B are those whereinR¹ is —CH(OH)-4-chlorophenyl, —CH(OH)-4-chloro-2-(hydroxymethyl)phenyl,—CH(OH)-3,4-dichlorophenyl, —CH(OH)-3,4-difluorophenyl,—CH(OH)-3-fluoro-4-chlorophenyl, —CH(OH)-3-methyl-4-chlorophenyl,—CH(OH)-3-fluoro-4-trifluoromethylphenyl,—CH(OH)-4-trifluoromethylphenyl, —CH(OH)-4-(trifluoromethoxy)phenyl,—CH(OH)-4-fluoro-3-trifluoromethylphenyl,—CH(OH)-benzo[d][1,3]dioxazole, —CH(OH)-4-isopropylphenyl, or—CH(OH)-3-chloro-4-fluorophenyl; R⁴ is —CH₃; and R⁵ is H.

In yet other preferred embodiments, the compounds of Formula I-B arethose wherein R¹ is —CH(OH)-4-chlorophenyl, —CH(OH)-3,4-dichlorophenyl,or —CH(OH)-3-methyl-4-chlorophenyl; R⁴ is —CH₃; and R⁵ is H or F.

In some preferred embodiments, the compounds of Formula I-B are thosewherein R¹ is —CH(OH)-4-chlorophenyl, —CH(OH)-3,4-dichlorophenyl,—CH(OH)-3,4-difluorophenyl, —CH(OH)-3-fluoro-4-chlorophenyl,—CH(OH)-3-chloro-4-fluorophenyl, —CH(OH)-3-methyl-4-chlorophenyl,—CH(OH)-3-fluoro-4-trifluoromethylphenyl, —C(Me)(OH)-4-chlorophenyl,—C(Me)(OH)-3,4-dichlorophenyl, —C(Me)(OH)-3,4-difluorophenyl,—C(Me)(OH)-3-fluoro-4-chlorophenyl, —C(Me)(OH)-3-chloro-4-fluorophenyl,—C(Me)(OH)-3-methyl-4-chlorophenyl, or—C(Me)(OH)-3-fluoro-4-trifluoromethylphenyl; R⁴ is —CH₃; and R⁵ is H.

In other preferred embodiments, the compounds of Formula I-B are thosewherein R¹ is —CH(OH)-4-chlorophenyl, —CH(OH)-3,4-dichlorophenyl,—CH(OH)-3-methyl-4-chlorophenyl, —CH(OH)-4-trifluoromethylphenyl,—CH(OH)-4-fluoro-3-trifluoromethylphenyl,—CH(OH)-3-fluoro-4-trifluoromethylphenyl,—CH(OH)-4-chloro-2-(hydroxymethyl)phenyl; R⁴ is —CH₃ and R⁵ is H.

In some preferred embodiments, the compounds of Formula I-B are thosewherein R¹ is —C₁-C₆alk-O-aryl, and R⁴ is —NR⁶R^(6′), —NH—O—R⁶ or—NH—NR⁶R^(6′); R⁵ is H or F; and R⁶ and R^(6′) are each independently Hor —C₁-C₆alkyl.

In other preferred embodiments, the compounds of Formula I-B are thosewherein R¹ is —C₁-C₆alk-O-aryl, R⁴ is —NH₂, —NH—O—CH₃ or —NH—NHCH₃; andR⁵ is H or F.

In other preferred embodiments, the compounds of Formula I-B are thosewherein R¹ is —CH₂—O-3-(aminomethyl)phenyl; R⁴ is —NH₂, —NH—O—CH₃ or—NH—NHCH₃; and R⁵ is H or F.

In some aspects, the present disclosure is directed to compounds ofFormula I-B wherein R¹ is —C₁-C₆alk-S—C₁-C₆alkyl, R⁴ is —NR⁶R^(6′),—NH—O—R⁶ or —NH—NR⁶R^(6′); and R⁶ and R^(6′) are each independently H or—C₁-C₆alkyl.

In some aspects, the present disclosure is directed to compounds ofFormula I-B wherein R¹ is —C₁-C₆alk-O—C₁-C₆alkyl, R⁴ is —NR⁶R^(6′),—NH—O—R⁶ or —NH—NR⁶R^(6′); and R⁶ and R^(6′) are each independently H or—C₁-C₆alkyl.

In some preferred embodiments, the present disclosure is directed tocompounds of Formula I-C

wherein R⁴ is —NR⁶R^(6′), —NH—O—R⁶ or —NH—NR⁶R^(6′); R⁵ is H or F; andR⁶ and R^(6′) are each independently H or —C₁-C₆alkyl. Other preferredembodiments are compounds of Formula I-C wherein R⁴ is —NR⁶R^(6′),—NH—O—R⁶ or —NH—NR⁶R^(6′); R⁵ is H or F; R⁶ and R^(6′) are eachindependently H or —C₁-C₆alkyl, and heteroaryl is quinolinyl,substituted quinolinyl, indolyl, substituted indolyl, indazolyl, orsubstituted indazolyl.

Other preferred embodiments are compounds of Formula I-C wherein R⁴ is—NH₂, —NH—O—CH₃ or —NH—NHCH₃; and R⁵ is H or F.

Other preferred embodiments are compounds of Formula I-C wherein R⁴ is—NH₂, —NH—OH, —NH—O—CH₃ or —NH—NHCH₃; R⁵ is H or F. R⁶ and R^(6′) areeach independently H or —C₁-C₆alkyl, and heteroaryl is quinolinyl,substituted quinolinyl, indolyl, substituted indolyl, indazolyl,substituted indazolyl, imidazo[1,2-a]pyridinyl, or substitutedimidazo[1,2-a]pyridinyl.

Other preferred embodiments are compounds of Formula I-C whereinheteroaryl is (2-amino-3-bromoquinolin-7-yl),(2-amino-3-chloroquinolin-7-yl), (2-amino-3-fluoroquinolin-7-yl),(2-(methylamino)quinolin-7-yl), (2-aminoquinolin-7-yl),2-(methoxyamino)quinolin-7-yl, (indol-6-yl), (indazol-6-yl), and R⁴ is—NR⁶R^(6′), —NH—O—R⁶ or —NH—NR⁶R^(6′); R⁵ is H or F; and R⁶ and R^(6′)are each independently H or —C₁-C₆alkyl.

Other preferred embodiments are compounds of Formula I-C whereinheteroaryl is (2-amino-3-bromoquinolin-7-yl),(2-amino-3-chloroquinolin-7-yl), (2-amino-3-fluoroquinolin-7-yl),(2-(methylamino)quinolin-7-yl), (2-aminoquinolin-7-yl), (indol-6-yl),(indazol-6-yl), and R⁴ is —NR⁶R^(6′), —NH—O—R⁶ or —NH—NR⁶R^(6′); R⁵ is Hor F; and R⁶ and R^(6′) are each independently H or —C₁-C₆alkyl.

Other preferred embodiments are compounds of Formula I-C whereinheteroaryl is quinolinyl, substituted quinolinyl, indolyl, substitutedindolyl, indazolyl, substituted indazolyl, imidazo[1,2-a]pyridinyl, orsubstituted imidazo[1,2-a]pyridinyl; R⁴ is —NR⁶R^(6′), —NH—O—R⁶ or—NH—NR⁶R^(6′); R⁵ is H or F; and R⁶ and R^(6′) are each independently Hor —C₁-C₆alkyl.

Other preferred embodiments are compounds of Formula I-C whereinheteroaryl is quinolin-7-yl, (2-amino-3-bromoquinolin-7-yl),(2-amino-3-chloroquinolin-7-yl), (2-amino-3-fluoroquinolin-7-yl),(2-(methylamino)quinolin-7-yl), (2-aminoquinolin-7-yl),2-(methoxyamino)quinolin-7-yl, (indol-6-yl), (indazol-6-yl), or(3-methylimidazo[1,2-a]pyridine-7yl); R⁴ is —NR⁶R^(6′), —NH—O—R⁶ or—NH—NR⁶R^(6′); R⁵ is H or F; and R⁶ and R^(6′) are each independently Hor —C₁-C₆alkyl.

In some preferred embodiments, the present disclosure is directed tocompounds of Formula I-D

wherein R⁴ is —NR⁶R^(6′), —NH—O—R⁶ or —NH—NR⁶R^(6′); R⁵ is H or F; andR⁶ and R^(6′) are each independently H or —C₁-C₆alkyl. Other preferredembodiments are compounds of Formula I-D wherein R⁴ is —NR⁶R^(6′),—NH—O—R⁶ or —NH—NR⁶R^(6′); R⁵ is H or F; R⁶ and R^(6′) are eachindependently H or —C₁-C₆alkyl, and aryl is phenyl or substitutedphenyl.

Some embodiments of compounds of formula I-D are those wherein R⁴ is—NR⁶R^(6′), —NH—O—R⁶ or —NH—NR⁶R^(6′); R⁵ is H or F; R⁶ and R^(6′) areeach independently H or —C₁-C₆alkyl, and aryl is a mono- orbicyclic-aromatic hydrocarbon ring structure having 6 or 10 carbon atomsin the ring, wherein one or more of the carbon atoms in the ring isoptionally substituted with a halogen atom, a —C₁-C₃ alkyl group, anamino-substituted —C₁-C₃ alkyl group, a C₁-C₃haloalkyl group, an aminogroup (i.e., —NH₂), or a substituted amino group.

Other preferred embodiments are compounds of Formula I-D wherein R⁴ is—NH₂, —NH—O—CH₃ or —NH—NHCH₃; and R⁵ is H or F.

Other preferred embodiments are compounds of Formula I-D wherein R⁴ is—NH₂, —NH—OH, —NH—O—CH₃ or —NH—NHCH₃; and R⁵ is H or F, R⁶ and R^(6′)are each independently H or —C₁-C₆alkyl, and aryl is phenyl orsubstituted phenyl.

Other preferred embodiments are compounds of Formula I-D wherein aryl is-4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl,-3-fluoro-4-chlorophenyl, -3-chloro-4-fluorophenyl,-3-methyl-4-chlorophenyl, -3-fluoro-4-trifluoromethylphenyl, R⁴ is—NR⁶R^(6′), —NH—O—R⁶ or —NH—NR⁶R^(6′); R⁵ is H or F; and R⁶ and R^(6′)are each independently H or —C₁-C₆alkyl.

Other preferred embodiments are compounds of Formula I-D wherein aryl is-4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl,-3-fluoro-4-chlorophenyl, -3-chloro-4-fluorophenyl,-3-methyl-4-chlorophenyl, -3-fluoro-4-trifluoromethylphenyl, or-4-fluoro-3-trifluoromethylphenyl, R⁴ is —NR⁶R^(6′), —NH—O—R⁶ or—NH—NR⁶R^(6′); R⁵ is H or F and R⁶ and R^(6′) are each independently Hor —C₁-C₆alkyl.

Yet other preferred embodiments are compounds of Formula I-D whereinaryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl,-3-fluoro-4-chlorophenyl, -3-chloro-4-fluorophenyl,-3-methyl-4-chlorophenyl, or -3-fluoro-4-trifluoromethylphenyl; R⁴ is—NH₂, —NH—O—CH₃ or —NH—NHCH₃; and R⁵ is H or F.

Other preferred embodiments are compounds of Formula I-D wherein aryl is-4-chlorophenyl, -4-chloro-2-(hydroxymethyl)phenyl, -3,4-dichlorophenyl,-3,4-difluorophenyl, -3-fluoro-4-chlorophenyl, -3-methyl-4-chlorophenyl,-3-fluoro-4-trifluoromethylphenyl, -4-trifluoromethylphenyl,-4-(trifluoromethoxy)phenyl, -4-fluoro-3-trifluoromethylphenyl,-benzo[d][1,3]dioxazole, -4-isopropylphenyl, or-3-chloro-4-fluorophenyl; R⁴ is —NH₂, —NH—O—CH₃ or —NH—NHCH₃; and R⁵ isH or F.

In some preferred embodiments, the present disclosure is directed tocompounds of Formula I-E

wherein R⁴ is —NR⁶R^(6′), —NH—O—R⁶ or —NH—NR⁶R^(6′); R¹ is H or F; andR⁶ and R^(6′) are each independently H or —C₁-C₆alkyl.

Other preferred embodiments are compounds of Formula I-E wherein R⁴ is—NH₂, —NHCH₃, —NH—O—CH₃ or —NH—NHCH₃; and R⁵ is H or F.

In some preferred embodiments, the present disclosure is directed tocompounds of Formula I-F

wherein R⁴ is —NR⁶R^(6′)—NH—O—R⁶ or —NH—NR⁶R^(6′); R⁵ is H or F; and R⁶and R^(6′) are each independently H or —C₁-C₆alkyl.

Other preferred embodiments are compounds of Formula I-F wherein R⁴ is—NH₂, —NHCH₃, —NH—O—CH₃ or —NH—NHCH₃; and R¹ is H or F.

In some preferred embodiments, the present disclosure is directed tocompounds of Formula I-G

wherein R¹ is —C₀-C₆alk-C₁-C₆alkyl, —C₀-C₆alk-C₁-C₆haloalkyl,—C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₆alk-S—C₁-C₆alkyl, —C₁-C₆alk-aryl,—C₁-C₆alk-O-aryl, —C₀-C₆alk-heteroaryl, —C₁-C₆alk-O-heteroaryl,—C₁-C₆alk-S-heteroaryl, or —C₁-C₆alk-NH-heteroaryl; and R⁵ is H or F.

In some embodiments, the compounds of Formula I-G are those wherein R¹is —C₁-C₆alk-aryl or —C₁-C₆alk-O-heteroaryl; and R⁵ is H or F.

In some embodiments, the compounds of Formula I-G are those wherein R¹is —C₁-C₆alk-aryl and R⁵ is H or F. In some embodiments, the compoundsof Formula I-G are those wherein R¹ is —C₁-C₆alk-aryl wherein aryl is amono- or bicyclic-aromatic hydrocarbon ring structure having 6 or 10carbon atoms in the ring, wherein one or more of the carbon atoms in thering is optionally substituted with a halogen atom, a —C₁-C₃ alkylgroup, an amino-substituted —C₁-C₃ alkyl group, a C₁-C₃haloalkyl group,an amino group (i.e., —NH₂), or a substituted amino group; and R⁵ is Hor F.

In some embodiments, the compounds of Formula I-G are those wherein R¹is —C₁-C₆alk-O-heteroaryl and R⁵ is H or F.

In other preferred embodiments, the present disclosure is directed tocompounds of Formula I-H

wherein R¹ is —C₀-C₆alk-C₁-C₆alkyl, —C₀-C₆alk-C₁-C₆haloalkyl,—C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₆alk-S—C₁-C₆alkyl, —C₁-C₆alk-aryl,—C₁-C₆alk-O-aryl, —C₀-C₆alk-heteroaryl, —C₁-C₆alk-O-heteroaryl,—C₁-C₆alk-S-heteroaryl, or —C₁-C₆alk-NH-heteroaryl; R⁵ is H or F; and R⁶and R^(6′) are each independently H or —C₁-C₆alkyl.

Some preferred embodiments are compounds of Formula I-H wherein R¹is-C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₆alk-S—C₁-C₆alkyl, —C₁-C₆alk-aryl,—C₀-C₆alk-heteroaryl, —C₁-C₆alk-O-heteroaryl, —C₁-C₆alk-S-heteroaryl, or—C₁-C₆alk-NH-heteroaryl; R⁵ is H or F; and R⁶ is H and R^(6′) is methyl.

In some embodiments, the compounds of Formula I-H are those wherein R¹is —C₁-C₆alk-aryl or —C₁-C₆alk-O-heteroaryl; and R⁵ is H or F, and R⁶and R^(6′) are each independently H or —C₁-C₆alkyl.

In some embodiments, the compounds of Formula I-H are those wherein R¹is —C₁-C₆alk-aryl; R⁵ is H or F; and R⁶ and R^(6′) are eachindependently H or —C₁-C₆alkyl. In some embodiments, the compounds ofFormula I-H are those wherein R¹ is —C₁-C₆alk-aryl wherein aryl is amono- or bicyclic-aromatic hydrocarbon ring structure having 6 or 10carbon atoms in the ring, wherein one or more of the carbon atoms in thering is optionally substituted with a halogen atom, a —C₁-C₃ alkylgroup, an amino-substituted —C₁-C₃ alkyl group, a C₁-C₃haloalkyl group,an amino group (i.e., —NH₂), or a substituted amino group; R⁵ is H or F;and R⁶ and R^(6′) are each independently H or —C₁-C₆alkyl.

In some embodiments, the compounds of Formula I-H are those wherein R¹is —C₁-C₆alk-O-heteroaryl; R⁵ is H or F; and R⁶ and R^(6′) are eachindependently H or —C₁-C₆alkyl.

In other preferred embodiments, the present disclosure is directed tocompounds of Formula I-J

wherein R¹ is —C₀-C₆alk-C₁-C₆alkyl, —C₀-C₆alk-C₁-C₆haloalkyl,—C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₆alk-S—C₁-C₆alkyl, —C₁-C₆alk-aryl,—C₁-C₆alk-O-aryl, —C₀-C₆alk-heteroaryl, —C₁-C₆alk-O-heteroaryl,—C₁-C₆alk-S-heteroaryl, or —C₁-C₆alk-NH-heteroaryl; R⁵ is H or F; and R⁶is H or —C₁-C₆alkyl.

Some preferred embodiments are compounds of Formula I-J whereinR¹—C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₆alk-S—C₁-C₆alkyl, —C₁-C₆alk-aryl,—C₀-C₆alk-heteroaryl, —C₁-C₆alk-O-heteroaryl, —C₁-C₆alk-S-heteroaryl, or—C₁-C₆alk-NH-heteroaryl; R⁵ is H or F; and R⁶ methyl.

In some embodiments, the compounds of Formula I-J are those wherein R¹is —C₁-C₆alk-aryl or —C₁-C₆alk-O-heteroaryl; and R⁵ is H or F; and R⁶and R^(6′) are each independently H or —C₁-C₆alkyl.

In some embodiments, the compounds of Formula I-J are those wherein R¹is —C₁-C₆alk-aryl; R⁵ is H or F; and R⁶ and R^(6′) are eachindependently H or —C₁-C₆alkyl. In some embodiments, the compounds ofFormula I-J are those wherein R¹ is —C₁-C₆alk-aryl wherein aryl is amono- or bicyclic-aromatic hydrocarbon ring structure having 6 or 10carbon atoms in the ring, wherein one or more of the carbon atoms in thering is optionally substituted with a halogen atom, a —C₁-C₃ alkylgroup, an amino-substituted —C₁-C₃ alkyl group, a C₁-C₃haloalkyl group,an amino group (i.e., —NH₂), or a substituted amino group; R⁵ is H or F;and R⁶ and R^(6′) are each independently H or —C₁-C₆alkyl.

In some embodiments, the compounds of Formula I-J are those wherein R¹is —C₁-C₆alk-O-heteroaryl; R⁵ is H or F; and R⁶ and R^(6′) are eachindependently H or —C₁-C₆alkyl.

References to Formula I herein also refer to Formulas I-A, I-B, I-C,I-D, I-E, I-F, I-G, I-H, and I-J.

Stereoisomers of compounds of Formula I are also contemplated by thepresent disclosure. Thus, the disclosure encompasses all stereoisomersand constitutional isomers of any compound disclosed or claimed herein,including all enantiomers and diastereomers.

Pharmaceutically acceptable salts and solvates of the compounds ofFormula I are also within the scope of the disclosure.

Isotopic variants of the compounds of Formula I are also contemplated bythe present disclosure.

Pharmaceutical Compositions and Methods of Administration

The subject pharmaceutical compositions are typically formulated toprovide a therapeutically effective amount of a compound of the presentdisclosure as the active ingredient, or a pharmaceutically acceptablesalt, ester, prodrug, solvate, hydrate or derivative thereof. Wheredesired, the pharmaceutical compositions contain pharmaceuticallyacceptable salt and/or coordination complex thereof, and one or morepharmaceutically acceptable excipients, carriers, including inert soliddiluents and fillers, diluents, including sterile aqueous solution andvarious organic solvents, permeation enhancers, solubilizers andadjuvants.

The subject pharmaceutical compositions can be administered alone or incombination with one or more other agents, which are also typicallyadministered in the form of pharmaceutical compositions. Where desired,the one or more compounds of the invention and other agent(s) may bemixed into a preparation or both components may be formulated intoseparate preparations to use them in combination separately or at thesame time.

In some embodiments, the concentration of one or more compounds providedin the pharmaceutical compositions of the present invention is less than100%, 90%, 80%, 70%, 60%, 500/a, 40%, 30/%, 20%, 19%⁰, 18%, 17%, 16%,15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%,0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%,0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%,0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%,0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or anumber in the range defined by and including any two numbers above) w/w,w/v or v/v.

In some embodiments, the concentration of one or more compounds of theinvention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%,17.25% 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25% 15%,14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%, 13%, 12.756, 12.50%,12.25%, 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%,9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%,7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%,4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%,1.50%, 1.25%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%,0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%,0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002/0, 0.001%,0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%,or 0.0001% (or a number in the range defined by and including any twonumbers above) w/w, w/v, or v/v.

In some embodiments, the concentration of one or more compounds of theinvention is in the range from approximately 0.0001% to approximately50%, approximately 0.001% to approximately 40%, approximately 0.01% toapproximately 30%, approximately 0.02% to approximately 29%,approximately 0.03% to approximately 280%, approximately 0.04% toapproximately 27%, approximately 0.05% to approximately 26%,approximately 0.06% to approximately 25%, approximately 0.07% toapproximately 24%, approximately 0.08% to approximately 23%,approximately 0.09% to approximately 22%, approximately 0.1% toapproximately 21%, approximately 0.2% to approximately 20%,approximately 0.3% to approximately 19%, approximately 0.4% toapproximately 18%, approximately 0.5% to approximately 17%,approximately 0.6% to approximately 16%, approximately 0.7% toapproximately 15%, approximately 0.8% to approximately 140%,approximately 0.9% to approximately 12%, approximately 1% toapproximately 10% w/w, w/v or v/v.

In some embodiments, the concentration of one or more compounds of theinvention is in the range from approximately 0.001% to approximately100%, approximately 0.01% to approximately 5%, approximately 0.02% toapproximately 4.5%, approximately 0.03% to approximately 4%,approximately 0.04% to approximately 3.5%, approximately 0.05% toapproximately 3%, approximately 0.06% to approximately 2.5%,approximately 0.07% to approximately 2%, approximately 0.08% toapproximately 1.5%, approximately 0.09% to approximately 1%,approximately 0.1% to approximately 0.9% w/w, w/v or v/v.

In some embodiments, the amount of one or more compounds of theinvention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g,2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g,0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g,0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g,0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g,0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g (or a number in therange defined by and including any two numbers above).

In some embodiments, the amount of one or more compounds of theinvention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g,0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g,0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g,0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g,0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g,7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g (or a number in the range definedby and including any two numbers above).

In some embodiments, the amount of one or more compounds of theinvention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

The compounds according to the invention are effective over a widedosage range. For example, in the treatment of adult humans, dosagesfrom 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, andfrom 5 to 40 mg per day are examples of dosages that may be used. Anexemplary dosage is 10 to 30 mg per day. The exact dosage will dependupon the route of administration, the form in which the compound isadministered, the subject to be treated, the body weight of the subjectto be treated, and the preference and experience of the attendingphysician.

A pharmaceutical composition of the invention typically contains anactive ingredient (i.e., a compound of the disclosure) of the presentinvention or a pharmaceutically acceptable salt and/or coordinationcomplex thereof, and one or more pharmaceutically acceptable excipients,carriers, including but not limited to inert solid diluents and fillers,diluents, sterile aqueous solution and various organic solvents,permeation enhancers, solubilizers and adjuvants.

Described below are non-limiting exemplary pharmaceutical compositionsand methods for preparing the same.

Pharmaceutical Compositions for Oral Administration.

In some embodiments, the invention provides a pharmaceutical compositionfor oral administration containing a compound of the invention, and apharmaceutical excipient suitable for oral administration.

In some embodiments, the invention provides a solid pharmaceuticalcomposition for oral administration containing: (i) an effective amountof a compound of the invention; optionally (ii) an effective amount of asecond agent; and (iii) a pharmaceutical excipient suitable for oraladministration. In some embodiments, the composition further contains:(iv) an effective amount of a third agent.

In some embodiments, the pharmaceutical composition may be a liquidpharmaceutical composition suitable for oral consumption. Pharmaceuticalcompositions of the invention suitable for oral administration can bepresented as discrete dosage forms, such as capsules, cachets, ortablets, or liquids or aerosol sprays each containing a predeterminedamount of an active ingredient as a powder or in granules, a solution,or a suspension in an aqueous or nonaqueous liquid, an oil-in-wateremulsion, or a water-in-oil liquid emulsion. Such dosage forms can beprepared by any of the methods of pharmacy, but all methods include thestep of bringing the active ingredient into association with thecarrier, which constitutes one or more necessary ingredients. Ingeneral, the compositions are prepared by uniformly and intimatelyadmixing the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product intothe desired presentation. For example, a tablet can be prepared bycompression or molding, optionally with one or more accessoryingredients. Compressed tablets can be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such aspowder or granules, optionally mixed with an excipient such as, but notlimited to, a binder, a lubricant, an inert diluent, and/or a surfaceactive or dispersing agent. Molded tablets can be made by molding in asuitable machine a mixture of the powdered compound moistened with aninert liquid diluent.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising an active ingredient, since water canfacilitate the degradation of some compounds. For example, water may beadded (e.g., 5%) in the pharmaceutical arts as a means of simulatinglong-term storage in order to determine characteristics such asshelf-life or the stability of formulations over time. Anhydrouspharmaceutical compositions and dosage forms of the invention can beprepared using anhydrous or low moisture containing ingredients and lowmoisture or low humidity conditions. Pharmaceutical compositions anddosage forms of the invention which contain lactose can be madeanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected. An anhydrouspharmaceutical composition may be prepared and stored such that itsanhydrous nature is maintained. Accordingly, anhydrous compositions maybe packaged using materials known to prevent exposure to water such thatthey can be included in suitable formulary kits. Examples of suitablepackaging include, but are not limited to, hermetically sealed foils,plastic or the like, unit dose containers, blister packs, and strippacks.

An active ingredient can be combined in an intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier can take a wide variety of formsdepending on the form of preparation desired for administration. Inpreparing the compositions for an oral dosage form, any of the usualpharmaceutical media can be employed as carriers, such as, for example,water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents, and the like in the case of oral liquid preparations(such as suspensions, solutions, and elixirs) or aerosols; or carrierssuch as starches, sugars, micro-crystalline cellulose, diluents,granulating agents, lubricants, binders, and disintegrating agents canbe used in the case of oral solid preparations, in some embodimentswithout employing the use of lactose. For example, suitable carriersinclude powders, capsules, and tablets, with the solid oralpreparations. If desired, tablets can be coated by standard aqueous ornonaqueous techniques.

Binders suitable for use in pharmaceutical compositions and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixturesthereof.

Examples of suitable fillers for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

Disintegrants may be used in the compositions of the invention toprovide tablets that disintegrate when exposed to an aqueousenvironment. Too much of a disintegrant may produce tablets which maydisintegrate in the bottle. Too little may be insufficient fordisintegration to occur and may thus alter the rate and extent ofrelease of the active ingredient(s) from the dosage form. Thus, asufficient amount of disintegrant that is neither too little nor toomuch to detrimentally alter the release of the active ingredient(s) maybe used to form the dosage forms of the compounds disclosed herein. Theamount of disintegrant used may vary based upon the type of formulationand mode of administration, and may be readily discernible to those ofordinary skill in the art. About 0.5 to about 15 weight percent ofdisintegrant, or about 1 to about 5 weight percent of disintegrant, maybe used in the pharmaceutical composition. Disintegrants that can beused to form pharmaceutical compositions and dosage forms of theinvention include, but are not limited to, agar-agar, alginic acid,calcium carbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, other starches, pre-gelatinized starch, other starches,clays, other algins, other celluloses, gums or mixtures thereof.

Lubricants which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel, a coagulated aerosol of synthetic silica, or mixturesthereof. A lubricant can optionally be added, in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient therein may be combined withvarious sweetening or flavoring agents, coloring matter or dyes and, ifso desired, emulsifying and/or suspending agents, together with suchdiluents as water, ethanol, propylene glycol, glycerin and variouscombinations thereof.

The tablets can be uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. Formulations for oral use can also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example, peanut oil, liquidparaffin or olive oil.

Surfactant which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to,hydrophilic surfactants, lipophilic surfactants, and mixtures thereof.That is, a mixture of hydrophilic surfactants may be employed, a mixtureof lipophilic surfactants may be employed, or a mixture of at least onehydrophilic surfactant and at least one lipophilic surfactant may beemployed.

A suitable hydrophilic surfactant may generally have an HLB value of atleast 10, while suitable lipophilic surfactants may generally have anHLB value of or less than about 10. An empirical parameter used tocharacterize the relative hydrophilicity and hydrophobicity of non-ionicamphiphilic compounds is the hydrophilic-lipophilic balance (“HLB”value). Surfactants with lower HLB values are more lipophilic orhydrophobic, and have greater solubility in oils, while surfactants withhigher HLB values are more hydrophilic, and have greater solubility inaqueous solutions.

Hydrophilic surfactants are generally considered to be those compoundshaving an HLB value greater than about 10, as well as anionic, cationic,or zwitterionic compounds for which the HLB scale is not generallyapplicable. Similarly, lipophilic (i.e., hydrophobic) surfactants arecompounds having an HLB value equal to or less than about 10. However,HLB value of a surfactant is merely a rough guide generally used toenable formulation of industrial, pharmaceutical and cosmetic emulsions.

Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionicsurfactants include, but are not limited to, alkylammonium salts;fusidic acid salts; fatty acid derivatives of amino acids,oligopeptides, and polypeptides; glyceride derivatives of amino acids,oligopeptides, and polypeptides; lecithins and hydrogenated lecithins;lysolecithins and hydrogenated lysolecithins; phospholipids andderivatives thereof; lysophospholipids and derivatives thereof;carnitine fatty acid ester salts; salts of alkylsulfates; fatty acidsalts; sodium docusate; acyl lactylates; mono- and diacetylated tartaricacid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures thereof.

Within the aforementioned group, ionic surfactants include, by way ofexample: lecithins, lysolecithin, phospholipids, lysophospholipids andderivatives thereof; carnitine fatty acid ester salts; salts ofalkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono-and diacetylated tartaric acid esters of mono- and di-glycerides;succinylated mono- and di-glycerides; citric acid esters of mono- anddi-glycerides; and mixtures thereof.

Ionic surfactants may be the ionized forms of lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof.

Hydrophilic non-ionic surfactants may include, but are not limited to,alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esterssuch as polyethylene glycol fatty acids monoesters and polyethyleneglycol fatty acids diesters; polyethylene glycol glycerol fatty acidesters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fattyacid esters such as polyethylene glycol sorbitan fatty acid esters;hydrophilic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylenesterols, derivatives, and analogues thereof; polyoxyethylated vitaminsand derivatives thereof; polyoxyethylene-polyoxypropylene blockcopolymers; and mixtures thereof; polyethylene glycol sorbitan fattyacid esters and hydrophilic transesterification products of a polyolwith at least one member of the group consisting of triglycerides,vegetable oils, and hydrogenated vegetable oils. The polyol may beglycerol, ethylene glycol, polyethylene glycol, sorbitol, propyleneglycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG-100 succinate, PEG-24 cholesterol,polyglyceryl-1Ooleate, Tween 40, Tween 60, sucrose monostearate, sucrosemono laurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG15-100 octyl phenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fattyalcohols; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; propylene glycol fatty acidesters; sorbitan fatty acid esters; polyethylene glycol sorbitan fattyacid esters; sterols and sterol derivatives; polyoxyethylated sterolsand sterol derivatives; polyethylene glycol alkyl ethers; sugar esters;sugar ethers; lactic acid derivatives of mono- and di-glycerides;hydrophobic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids and sterols; oil-solublevitamins/vitamin derivatives; and mixtures thereof. Within this group,preferred lipophilic surfactants include glycerol fatty acid esters,propylene glycol fatty acid esters, and mixtures thereof, or arehydrophobic transesterification products of a polyol with at least onemember of the group consisting of vegetable oils, hydrogenated vegetableoils, and triglycerides.

In one embodiment, the composition may include a solubilizer to ensuregood solubilization and/or dissolution of the compound of the presentinvention and to minimize precipitation of the compound of the presentinvention. This can be especially important for compositions fornon-oral use, e.g., compositions for injection. A solubilizer may alsobe added to increase the solubility of the hydrophilic drug and/or othercomponents, such as surfactants, or to maintain the composition as astable or homogeneous solution or dispersion.

Examples of suitable solubilizers include, but are not limited to, thefollowing: alcohols and polyols, such as ethanol, isopropanol, butanol,benzyl alcohol, ethylene glycol, propylene glycol, butanediols andisomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydroxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives;ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol) or methoxy PEG; amides and other nitrogen-containingcompounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esterssuch as ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactoneand isomers thereof, β-butyrolactone and isomers thereof; and othersolubilizers known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, and water.

Mixtures of solubilizers may also be used. Examples include, but notlimited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide. Particularlypreferred solubilizers include sorbitol, glycerol, triacetin, ethylalcohol, PEG-400, glycofurol and propylene glycol.

The amount of solubilizer that can be included is not particularlylimited. The amount of a given solubilizer may be limited to abioacceptable amount, which may be readily determined by one of skill inthe art. In some circumstances, it may be advantageous to includeamounts of solubilizers far in excess of bioacceptable amounts, forexample to maximize the concentration of the drug, with excesssolubilizer removed prior to providing the composition to a subjectusing conventional techniques, such as distillation or evaporation.Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%,50%), 100%, or up to about 200%>by weight, based on the combined weightof the drug, and other excipients. If desired, very small amounts ofsolubilizer may also be used, such as 5%>, 2%>, 1%) or even less.Typically, the solubilizer may be present in an amount of about 1%>toabout 100%, more typically about 5%>to about 25%>by weight.

The composition can further include one or more pharmaceuticallyacceptable additives and excipients. Such additives and excipientsinclude, without limitation, detackifiers, anti-foaming agents,buffering agents, polymers, antioxidants, preservatives, chelatingagents, viscomodulators, tonicifiers, flavorants, colorants, odorants,opacifiers, suspending agents, binders, fillers, plasticizers,lubricants, and mixtures thereof.

In addition, an acid or a base may be incorporated into the compositionto facilitate processing, to enhance stability, or for other reasons.Examples of pharmaceutically acceptable bases include amino acids, aminoacid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide,sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate,magnesium hydroxide, magnesium aluminum silicate, synthetic aluminumsilicate, synthetic hydrocalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamine, trimethylamine,tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable arebases that are salts of a pharmaceutically acceptable acid, such asacetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonicacid, amino acids, ascorbic acid, benzoic acid, boric acid, butyricacid, carbonic acid, citric acid, fatty acids, formic acid, fumaricacid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lacticacid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionicacid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinicacid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonicacid, uric acid, and the like. Salts of polyprotic acids, such as sodiumphosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphatecan also be used. When the base is a salt, the cation can be anyconvenient and pharmaceutically acceptable cation, such as ammonium,alkali metals, alkaline earth metals, and the like. Example may include,but not limited to, sodium, potassium, lithium, magnesium, calcium andammonium.

Suitable acids are pharmaceutically acceptable organic or inorganicacids. Examples of suitable inorganic acids include hydrochloric acid,hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boricacid, phosphoric acid, and the like. Examples of suitable organic acidsinclude acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid, uric acid and the like.

Pharmaceutical Compositions for Injection.

In some embodiments, the invention provides a pharmaceutical compositionfor injection containing a compound of the present invention and apharmaceutical excipient suitable for injection. Components and amountsof agents in the compositions are as described herein.

The forms in which the novel compositions of the present invention maybe incorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and thelike (and suitable mixtures thereof), cyclodextrin derivatives, andvegetable oils may also be employed. The proper fluidity can bemaintained, for example, by the use of a coating, such as lecithin, forthe maintenance of the required particle size in the case of dispersionand by the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating the compoundof the present invention in the required amount in the appropriatesolvent with various other ingredients as enumerated above, as required,followed by filtered sterilization. Generally, dispersions are preparedby incorporating the various sterilized active ingredients into asterile vehicle which contains the basic dispersion medium and therequired other ingredients from those enumerated above. In the case ofsterile powders for the preparation of sterile injectable solutions,certain desirable methods of preparation are vacuum-drying andfreeze-drying techniques which yield a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Pharmaceutical Compositions for Topical (e.g. Transdermal) Delivery.

In some embodiments, the invention provides a pharmaceutical compositionfor transdermal delivery containing a compound of the present inventionand a pharmaceutical excipient suitable for transdermal delivery.

Compositions of the present invention can be formulated intopreparations in solid, semisolid, or liquid forms suitable for local ortopical administration, such as gels, water soluble jellies, creams,lotions, suspensions, foams, powders, slurries, ointments, solutions,oils, pastes, suppositories, sprays, emulsions, saline solutions,dimethylsulfoxide (DMSO)-based solutions. In general, carriers withhigher densities are capable of providing an area with a prolongedexposure to the active ingredients. In contrast, a solution formulationmay provide more immediate exposure of the active ingredient to thechosen area.

The pharmaceutical compositions also may comprise suitable solid or gelphase carriers or excipients, which are compounds that allow increasedpenetration of, or assist in the delivery of, therapeutic moleculesacross the stratum corneum permeability barrier of the skin. There aremany of these penetration-enhancing molecules known to those trained inthe art of topical formulation.

Examples of such carriers and excipients include, but are not limitedto, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols(e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g.,isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerolmonolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides,alkanes, alkanols, water, calcium carbonate, calcium phosphate, varioussugars, starches, cellulose derivatives, gelatin, and polymers such aspolyethylene glycols.

Another exemplary formulation for use in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of a compound of the present invention in controlled amounts,either with or without another agent.

The construction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art. See, e.g., U.S. Pat.Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructedfor continuous, pulsatile, or on demand delivery of pharmaceuticalagents.

Pharmaceutical Compositions for Inhalation.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices that deliver the formulationin an appropriate manner.

Other Pharmaceutical Compositions.

Pharmaceutical compositions may also be prepared from compositionsdescribed herein and one or more pharmaceutically acceptable excipientssuitable for sublingual, buccal, rectal, intraosseous, intraocular,intranasal, epidural, or intraspinal administration. Preparations forsuch pharmaceutical compositions are well-known in the art. See, e.g.,Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds.,Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Prattand Taylor, eds., Principles of Drug Action, Third Edition, ChurchillLivingston, N.Y., 1990; Katzung, ed., Basic and Clinical Pharmacology,Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., ThePharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001;Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams &Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-SecondEdition (The Pharmaceutical Press, London, 1999); all of which areincorporated by reference herein in their entirety.

Administration of the compounds or pharmaceutical composition of thepresent invention can be effected by any method that enables delivery ofthe compounds to the site of action. These methods include oral routes,intraduodenal routes, parenteral injection (including intravenous,intraarterial, subcutaneous, intramuscular, intravascular,intraperitoneal or infusion), topical (e.g. transdermal application),rectal administration, via local delivery by catheter or stent orthrough inhalation. Compounds can also be administered intraadiposallyor intrathecally.

The amount of the compound administered will be dependent on the subjectbeing treated, the severity of the disorder or condition, the rate ofadministration, the disposition of the compound and the discretion ofthe prescribing physician. However, an effective dosage is in the rangeof about 0.001 to about 100 mg per kg body weight per day, preferablyabout 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kghuman, this would amount to about 0.05 to 7 g/day, preferably about 0.05to about 2.5 g/day. In some instances, dosage levels below the lowerlimit of the aforesaid range may be more than adequate, while in othercases still larger doses may be employed without causing any harmfulside effect, e.g. by dividing such larger doses into several small dosesfor administration throughout the day.

In some embodiments, a compound of the invention is administered in asingle dose.

Typically, such administration will be by injection, e.g., intravenousinjection, in order to introduce the agent quickly. However, otherroutes may be used as appropriate. A single dose of a compound of theinvention may also be used for treatment of an acute condition.

In some embodiments, a compound of the invention is administered inmultiple doses. Dosing may be about once, twice, three times, fourtimes, five times, six times, or more than six times per day. Dosing maybe about once a month, once every two weeks, once a week, or once everyother day. In another embodiment a compound of the invention and anotheragent are administered together about once per day to about 6 times perday. In another embodiment the administration of a compound of theinvention and an agent continues for less than about 7 days. In yetanother embodiment the administration continues for more than about 6,10, 14, 28 days, two months, six months, or one year. In some cases,continuous dosing is achieved and maintained as long as necessary.

Administration of the compounds of the invention may continue as long asnecessary. In some embodiments, a compound of the invention isadministered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In someembodiments, a compound of the invention is administered for less than28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound ofthe invention is administered chronically on an ongoing basis, e.g., forthe treatment of chronic effects.

An effective amount of a compound of the invention may be administeredin either single or multiple doses by any of the accepted modes ofadministration of agents having similar utilities, including rectal,buccal, intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, or as an inhalant.

The compositions of the invention may also be delivered via animpregnated or coated device such as a stent, for example, or anartery-inserted cylindrical polymer. Such a method of administrationmay, for example, aid in the prevention or amelioration of restenosisfollowing procedures such as balloon angioplasty. Without being bound bytheory, compounds of the invention may slow or inhibit the migration andproliferation of smooth muscle cells in the arterial wall whichcontribute to restenosis. A compound of the invention may beadministered, for example, by local delivery from the struts of a stent,from a stent graft, from grafts, or from the cover or sheath of a stent.In some embodiments, a compound of the invention is admixed with amatrix. Such a matrix may be a polymeric matrix, and may serve to bondthe compound to the stent. Polymeric matrices suitable for such use,include, for example, lactone-based polyesters or copolyesters such aspolylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides,polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester)copolymers (e.g. PEO-PLLA); polydimethylsiloxane,poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g.polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone),fluorinated polymers such as polytetrafluoroethylene and celluloseesters. Suitable matrices may be nondegrading or may degrade with time,releasing the compound or compounds. Compounds of the invention may beapplied to the surface of the stent by various methods such as dip/spincoating, spray coating, dip-coating, and/or brush-coating. The compoundsmay be applied in a solvent and the solvent may be allowed to evaporate,thus forming a layer of compound onto the stent. Alternatively, thecompound may be located in the body of the stent or graft, for examplein microchannels or micropores. When implanted, the compound diffusesout of the body of the stent to contact the arterial wall. Such stentsmay be prepared by dipping a stent manufactured to contain suchmicropores or microchannels into a solution of the compound of theinvention in a suitable solvent, followed by evaporation of the solvent.Excess drug on the surface of the stent may be removed via an additionalbrief solvent wash. In yet other embodiments, compounds of the inventionmay be covalently linked to a stent or graft. A covalent linker may beused which degrades in vivo, leading to the release of the compound ofthe invention. Any bio-labile linkage may be used for such a purpose,such as ester, amide or anhydride linkages. Compounds of the inventionmay additionally be administered intravascularly from a balloon usedduring angioplasty. Extravascular administration of the compounds viathe pericard or via advential application of formulations of theinvention may also be performed to decrease restenosis.

A variety of stent devices which may be used as described are disclosed,for example, in the following references, all of which are herebyincorporated by reference: U.S. Pat. Nos. 5,451,233; 5,040,548;5,061,273; 5,496,346; 5,292,331; 5,674,278; 3,657,744; 4,739,762;5,195,984; 5,292,331; 5,674,278; 5,879,382; 6,344,053.

The compounds of the invention may be administered in dosages. It isknown in the art that due to intersubject variability in compoundpharmacokinetics, individualization of dosing regimen is necessary foroptimal therapy. Dosing for a compound of the invention may be found byroutine experimentation in light of the instant disclosure.

When a compound of the invention is administered in a composition thatcomprises one or more agents, and the agent has a shorter half-life thanthe compound of the invention unit dose forms of the agent and thecompound of the invention may be adjusted accordingly.

The subject pharmaceutical composition may, for example, be in a formsuitable for oral administration as a tablet, capsule, pill, powder,sustained release formulations, solution, suspension, for parenteralinjection as a sterile solution, suspension or emulsion, for topicaladministration as an ointment or cream or for rectal administration as asuppository. The pharmaceutical composition may be in unit dosage formssuitable for single administration of precise dosages. Thepharmaceutical composition will include a conventional pharmaceuticalcarrier or excipient and a compound according to the invention as anactive ingredient. In addition, it may include other medicinal orpharmaceutical agents, carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compound in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Methods of Use

The method typically comprises administering to a subject atherapeutically effective amount of a compound of the invention. Thetherapeutically effective amount of the subject combination of compoundsmay vary depending upon the intended application (in vitro or in vivo),or the subject and disease condition being treated, e.g., the weight andage of the subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that willinduce a particular response in target cells, e.g., reduction ofproliferation or downregulation of activity of a target protein. Thespecific dose will vary depending on the particular compounds chosen,the dosing regimen to be followed, whether it is administered incombination with other compounds, timing of administration, the tissueto which it is administered, and the physical delivery system in whichit is carried.

As used herein, the term “IC₅₀” refers to the half maximal inhibitoryconcentration of an inhibitor in inhibiting biological or biochemicalfunction. This quantitative measure indicates how much of a particularinhibitor is needed to inhibit a given biological process (or componentof a process, i.e. an enzyme, cell, cell receptor or microorganism) byhalf. In other words, it is the half maximal (50%) inhibitoryconcentration (IC) of a substance (50% IC, or IC50). EC50 refers to theplasma concentration required for obtaining 50%>of a maximum effect invivo.

In some embodiments, the subject methods utilize a PRMT5 inhibitor withan IC50 value of about or less than a predetermined value, asascertained in an in vitro assay. In some embodiments, the PRMT5inhibitor inhibits PRMT5 a with an IC50 value of about 1 nM or less, 2nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less,80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM orless, 150 nM or less, 160 nM or less, 170 nM or less, 180 nM or less,190 nM or less, 200 nM or less, 225 nM or less, 250 nM or less, 275 nMor less, 300 nM or less, 325 nM or less, 350 nM or less, 375 nM or less,400 nM or less, 425 nM or less, 450 nM or less, 475 nM or less, 500 nMor less, 550 nM or less, 600 nM or less, 650 nM or less, 700 nM or less,750 nM or less, 800 nM or less, 850 nM or less, 900 nM or less, 950 nMor less, 1 μM or less, 1.1 μM or less, 1.2 μM or less, 1.3 μM or less,1.4 μM or less, 1.5 μM or less, 1.6 μM or less, 1.7 μM or less, 1.8 μMor less, 1.9 μM or less, 2 μM or less, 5 μM or less, 10 μM or less, 15μM or less, 20 μM or less, 25 μM or less, 30 μM or less, 40 μM or less,50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, or500 μM, or less, (or a number in the range defined by and including anytwo numbers above).

In some embodiments, the PRMT5 inhibitor selectively inhibits PRMT5 awith an IC50 value that is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20,25, 30, 35, 40, 45, 50, 100, or 1000 times less (or a number in therange defined by and including any two numbers above) than its IC50value against one, two, or three other PRMTs.

In some embodiments, the PRMT5 inhibitor selectively inhibits PRMT5 awith an IC50 value that is less than about 1 nM, 2 nM, 5 nM, 7 nM, 10nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 120nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 225 nM, 250nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM, 400 nM, 425 nM, 450 nM, 475nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900nM, 950 nM, 1 μM, 1.1 μM, 1.2 μM, 1.3 μM, 1.4 μM, 1.5 μM, 1.6 μM, 1.7μM, 1.8 μM, 1.9 μM, 2 μM, 5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 40μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM,or 500 μM (or in the range defined by and including any two numbersabove), and said IC50 value is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15,20, 25, 30, 35, 40, 45, 50, 100, or 1000 times less (or a number in therange defined by and including any two numbers above) than its IC50value against one, two or three other PRMTs.

The subject methods are useful for treating a disease conditionassociated with PRMT5. Any disease condition that results directly orindirectly from an abnormal activity or expression level of PRMT5 can bean intended disease condition.

Different disease conditions associated with PRMT5 have been reported.PRMT5 has been implicated, for example, in a variety of human cancers aswell as a number of hemoglobinopathies.

Non-limiting examples of such conditions include but are not limited toAcanthoma, Acinic cell carcinoma, Acoustic neuroma, Acral lentiginousmelanoma, Acrospiroma, Acute eosinophilic leukemia, Acute lymphoblasticleukemia, Acute lymphocytic leukemia, Acute megakaryoblastic leukemia,Acute monocytic leukemia, Acute myeloblasts leukemia with maturation,Acute myeloid dendritic cell leukemia, Acute myeloid leukemia, Acutemyelogenous leukemia, Acute promyelocytic leukemia, Adamantinoma,Adenocarcinoma, Adenoid cystic carcinoma, Adenoma, Adenomatoidodontogenic tumor, Adrenocortical carcinoma, Adult T-cell leukemia,Aggressive NK-cell leukemia, AIDS-Related Cancers, AIDS-relatedlymphoma, Alveolar soft part sarcoma, Ameloblastic fibroma, Anal cancer,Anaplastic large cell lymphoma, Anaplastic thyroid cancer,Angioimmunoblastic T-cell lymphoma, Angiomyolipoma, Angiosarcoma,Appendix cancer, Astrocytoma, Atypical teratoid rhabdoid tumor, Basalcell carcinoma, Basal-like carcinoma, B-cell leukemia, B-cell lymphoma,Bellini duct carcinoma, Biliary tract cancer, Bladder cancer, Blastoma,Bone Cancer, Bone tumor, Brain Stem Glioma, Brain Tumor, Breast Cancer,Brenner tumor, Bronchial Tumor, Bronchioloalveolar carcinoma, Browntumor, Burkitt's lymphoma, Cancer of Unknown Primary Site, CarcinoidTumor, Carcinoma, Carcinoma in situ, Carcinoma of the penis, Carcinomaof Unknown Primary Site, Carcinosarcoma, Castleman's Disease, CentralNervous System Embryonal Tumor, Cerebellar Astrocytoma, CerebralAstrocytoma, Cervical Cancer, Cholangiocarcinoma, Chondroma,Chondrosarcoma, Chordoma, Choriocarcinoma, Choroid plexus papilloma,Chronic Lymphocytic Leukemia, Chronic monocytic leukemia, Chronicmyelogenous leukemia, Chronic Myeloproliferative Disorder, Chronicneutrophilic leukemia, Clear-cell tumor, Colon Cancer, Colorectalcancer, Craniopharyngioma, Cutaneous T-cell lymphoma, Degos disease,Dermatofibrosarcoma protuberans, Dermoid cyst, Desmoplastic small roundcell tumor, Diffuse large B cell lymphoma, Dysembryoplasticneuroepithelial tumor, Embryonal carcinoma, Endodermal sinus tumor,Endometrial cancer, Endometrial Uterine Cancer, Endometrioid tumor,Enteropathy-associated T-cell lymphoma, Ependymoblastoma, Ependymoma,Epidermoid cancer, Epithelioid sarcoma, Erythroleukemia, Esophagealcancer, Esthesioneuroblastoma, Ewing Family of Tumor, Ewing FamilySarcoma, Ewing's sarcoma, Extracranial Germ Cell Tumor, ExtragonadalGerm Cell Tumor, Extrahepatic Bile Duct Cancer, Extramammary Paget'sdisease, Fallopian tube cancer, Fetus in fetu, Fibroma, Fibrosarcoma,Follicular lymphoma, Follicular thyroid cancer, Gallbladder Cancer,Gallbladder cancer, Ganglioglioma, Ganglioneuroma, Gastric Cancer,Gastric lymphoma, Gastrointestinal cancer, Gastrointestinal CarcinoidTumor, Gastrointestinal Stromal Tumor, Gastrointestinal stromal tumor,Germ cell tumor, Germinoma, Gestational choriocarcinoma, GestationalTrophoblastic Tumor, Giant cell tumor of bone, Glioblastoma multiforme,Glioma, Gliomatosis cerebri, Glomus tumor, Glucagonoma, Gonadoblastoma,Granulosa cell tumor, Hairy Cell Leukemia, Head and Neck Cancer, Headand neck cancer, Heart cancer, Hemoglobinopathies such as b-thalassemiaand sickle cell disease (SCD), Hemangioblastoma, Hemangiopericytoma,Hemangiosarcoma, Hematological malignancy, Hepatocellular carcinoma,Hepatosplenic T-cell lymphoma, Hereditary breast-ovarian cancersyndrome, Hodgkin Lymphoma, Hodgkin's lymphoma, Hypopharyngeal Cancer,Hypothalamic Glioma, Inflammatory breast cancer, Intraocular Melanoma,Islet cell carcinoma, Islet Cell Tumor, Juvenile myelomonocyticleukemia, Kaposi Sarcoma, Kaposi's sarcoma, Kidney Cancer, Klatskintumor, Krukenberg tumor, Laryngeal Cancer, Laryngeal cancer, Lentigomaligna melanoma, Leukemia, Lip and Oral Cavity Cancer, Liposarcoma,Lung cancer, Luteoma, Lymphangioma, Lymphangiosarcoma,Lymphoepithelioma, Lymphoid leukemia, Lymphoma, Macroglobulinemia,Malignant Fibrous Histiocytoma, Malignant fibrous histiocytoma,Malignant Fibrous Histiocytoma of Bone, Malignant Glioma, MalignantMesothelioma, Malignant peripheral nerve sheath tumor, Malignantrhabdoid tumor, Malignant triton tumor, MALT lymphoma, Mantle celllymphoma, Mast cell leukemia, Mastocytosis, Mediastinal germ cell tumor,Mediastinal tumor, Medullary thyroid cancer, Medulloblastoma,Medulloblastoma, Medulloepithelioma, Melanoma, Melanoma, Meningioma,Merkel Cell Carcinoma, Mesothelioma, Mesothelioma, Metastatic SquamousNeck Cancer with Occult Primary, Metastatic urothelial carcinoma, MixedMullerian tumor, Monocytic leukemia, Mouth Cancer, Mucinous tumor,Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma, Multiplemyeloma, Mycosis Fungoides, Mycosis fungoides, Myelodysplasia Disease,Myelodysplasia Syndromes, Myeloid leukemia, Myeloid sarcoma,Myeloproliferative Disease, Myxoma, Nasal Cavity Cancer, NasopharyngealCancer, Nasopharyngeal carcinoma, Neoplasm, Neurinoma, Neuroblastoma,Neuroblastoma, Neurofibroma, Neuroma, Nodular melanoma, Non-HodgkinLymphoma, Non-Hodgkin lymphoma, Nonmelanoma Skin Cancer, Non-Small CellLung Cancer, Ocular oncology, Oligoastrocytoma, Oligodendroglioma,Oncocytoma, Optic nerve sheath meningioma. Oral Cancer, Oral cancer,Oropharyngeal Cancer, Osteosarcoma, Osteosarcoma, Ovarian Cancer,Ovarian cancer, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor,Ovarian Low Malignant Potential Tumor, Paget's disease of the breast,Pancoast tumor, Pancreatic Cancer, Pancreatic cancer, Papillary thyroidcancer, Papillomatosis, Paraganglioma, Paranasal Sinus Cancer,Parathyroid Cancer, Penile Cancer, Perivascular epithelioid cell tumor,Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumor ofIntermediate Differentiation, Pineoblastoma, Pituicytoma, Pituitaryadenoma, Pituitary tumor, Plasma Cell Neoplasm, Pleuropulmonaryblastoma, Polyembryoma, Precursor T-lymphoblastic lymphoma, Primarycentral nervous system lymphoma, Primary effusion lymphoma, PrimaryHepatocellular Cancer, Primary Liver Cancer, Primary peritoneal cancer,Primitive neuroectodermal tumor, Prostate cancer, Pseudomyxomaperitonei, Rectal Cancer, Renal cell carcinoma, Respiratory TractCarcinoma Involving the NUT Gene onChromosome 15, Retinoblastoma,Rhabdomyoma, Rhabdomyosarcoma, Richter's transformation, Sacrococcygealteratoma, Salivary Gland Cancer, Sarcoma, Schwannomatosis, Sebaceousgland carcinoma, Secondary neoplasm, Seminoma, Serous tumor,Sertoli-Leydig cell tumor, Sex cord-stromal tumor, Sezary Syndrome,Signet ring cell carcinoma, Skin Cancer, Small blue round cell tumor,Small cell carcinoma, Small Cell Lung Cancer, Small cell lymphoma, Smallintestine cancer, Soft tissue sarcoma, Somatostatinoma, Soot wart,Spinal Cord Tumor, Spinal tumor, Splenic marginal zone lymphoma,Squamous cell carcinoma, Stomach cancer, Superficial spreading melanoma,Supratentorial Primitive Neuroectodermal Tumor, Surfaceepithelial-stromal tumor, Synovial sarcoma, T-cell acute lymphoblasticleukemia, T-cell large granular lymphocyte leukemia, T-cell leukemia,T-cell lymphoma, T-cell prolymphocytic leukemia, Teratoma, Terminallymphatic cancer, Testicular cancer, Thecoma, Throat Cancer, ThymicCarcinoma, Thymoma, Thyroid cancer, Transitional Cell Cancer of RenalPelvis and Ureter, Transitional cell carcinoma, Urachal cancer, Urethralcancer, Urogenital neoplasm, Uterine sarcoma, Uveal melanoma, VaginalCancer, Verner Morrison syndrome, Verrucous carcinoma, Visual PathwayGlioma, Vulvar Cancer, Waldenstrom's macroglobulinemia, Warthin's tumor,Wilms' tumor, or any combination thereof.

In some embodiments, said method is for treating a disease selected fromthe group consisting of tumor angiogenesis, chronic inflammatory diseasesuch as rheumatoid arthritis, atherosclerosis, inflammatory boweldisease, skin diseases such as psoriasis, eczema, and scleroderma,diabetes, diabetic retinopathy, retinopathy of prematurity, age-relatedmacular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

In some embodiments, said method is for treating a disease selected frombreast cancer, lung cancer, pancreatic cancer, prostate cancer, coloncancer, ovarian cancer, uterine cancer, cervical cancer, leukemia suchas acute myeloid leukemia (AML), acute lymphocytic leukemia, chroniclymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia,myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia(AML), chronic myelogenous leukemia (CML), mastocytosis, chroniclymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplasticsyndrome (MDS), epidermoid cancer, or hemoglobinopathies such asb-thalassemia and sickle cell disease (SCD).

In other embodiments, said method is for treating a disease selectedfrom breast cancer, lung cancer, pancreatic cancer, prostate cancer,colon cancer, ovarian cancer, uterine cancer, or cervical cancer.

In other embodiments, said method is for treating a disease selectedfrom leukemia such as acute myeloid leukemia (AML), acute lymphocyticleukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairycell leukemia, myelodysplasia, myeloproliferative disorders, acutemyelogenous leukemia (AML), chronic myelogenous leukemia (CML),mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM),myelodysplastic syndrome (MDS), epidermoid cancer, or hemoglobinopathiessuch as b-thalassemia and sickle cell disease (SCD).

In yet other embodiments, said method is for treating a disease selectedfrom CDKN2A deleted cancers; 9P deleted cancers; MTAP deleted cancers;glioblastoma, NSCLC, head and neck cancer, bladder cancer, orhepatocellular carcinoma.

Compounds of the disclosure, as well as pharmaceutical compositionscomprising them, can be administered to treat any of the describeddiseases, alone or in combination with a medical therapy. Medicaltherapies include, for example, surgery and radiotherapy (e.g.,gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy,proton therapy, brachytherapy, systemic radioactive isotopes).

In other aspects, compounds of the disclosure, as well as pharmaceuticalcompositions comprising them, can be administered to treat any of thedescribed diseases, alone or in combination with one or more otheragents.

In other methods, the compounds of the disclosure, as well aspharmaceutical compositions comprising them, can be administered incombination with agonists of nuclear receptors agents.

In other methods, the compounds of the disclosure, as well aspharmaceutical compositions comprising them, can be administered incombination with antagonists of nuclear receptors agents.

In other methods, the compounds of the disclosure, as well aspharmaceutical compositions comprising them, can be administered incombination with an anti-proliferative agent.

In other aspects, compounds of the disclosure, as well as pharmaceuticalcompositions comprising them, can be administered to treat any of thedescribed diseases, alone or in combination with one or more otherchemotherapeutic agents. Examples of other chemotherapeutic agentsinclude, for example, abarelix, aldesleukin, alemtuzumab, alitretinoin,allopurinol, all-trans retinoic acid, altretamine, anastrozole, arsenictrioxide, asparaginase, azacitidine, bendamustine, bevacizumab,bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous,busulfan oral, calusterone, capecitabine, carboplatin, carmustine,cetuximab, chlorambucil, cisplatin, cladribine, clofarabine,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparinsodium, dasatinib, daunorubicin, decitabine, denileukin, denileukindiftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, fentanyl citrate, filgrastim,floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib,gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelinacetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinibmesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine,methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone,nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin,paclitaxel, pamidronate, panobinostat, panitumumab, pegaspargase,pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin,procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib,sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen,temozolomide, teniposide, testolactone, thalidomide, thioguanine,thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin,uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine,vorinstat, and zoledronate, as well as any combination thereof.

In other aspects, the other agent is a therapeutic agent that targets anepigenetic regulator. Examples of epigenetic regulator agentss include,for example, bromodomain inhibitors, the histone lysinemethyltransferases, histone arginine methyl transferases, histonedemethylases, histone deacetylases, histone acetylases, and DNAmethyltransferases, as well as any combination thereof. Histonedeacetylase inhibitors are preferred in some aspects, and include, forexample, vorinostat.

In other methods wherein the disease to be treated is cancer or anotherproliferative disease, the compounds of the disclosure, as well aspharmaceutical compositions comprising them, can be administered incombination with targeted therapy agents. Targeted therapies include,for example, JAK kinase inhibitors (e.g. Ruxolitinib), PI3 kinaseinhibitors (including PI3K-delta selective and broad spectrum PI3Kinhibitors), MEK inhibitors, Cyclin Dependent kinase inhibitors (e.g,CDK4/6 inhibitors), BRAF inhibitors, mTOR inhibitors, proteasomeinhibitors (e.g., Bortezomib, Carfilzomib), HDAC-inhibitors (e.g.,panobinostat, vorinostat), DNA methyl transferase inhibitors,dexamethasone, bromo and extra terminal family members, BTK inhibitors(e.g., ibrutinib, acalabrutinib), BCL2 inhibitors (e.g. venetoclax),MCL1 inhibitors, PARP inhibitors, FLT3 inhibitors, and LSD1 inhibitors,as well as any combination thereof.

In other methods wherein the disease to be treated is cancer or anotherproliferative disease, the compounds of the disclosure, as well aspharmaceutical compositions comprising them, can be administered incombination with an immune checkpoint inhibitor agents. Immunecheckpoint inhibitors include, for example, inhibitors of PD-1, forexample, an anti-PD-1 monoclonal antibody. Examples of anti-PD-1monoclonal antibodies include, for example, nivolumab, pembrolizumab(also known as MK-3475), pidilizumab, SHR-1210, PDR001, and AMP-224, aswell as combinations thereof. In some aspects, the anti-PD1 antibody isnivolumab. In some aspects, the anti-PD1 antibody is pembrolizumab. Insome aspects, the immunce checkpoint inhibitor is an inhibitor of PD-L1,for example, an anti-PD-L1 monoclonal antibody. In some aspects, theanti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (alsoknown as RG7446), or MSB0010718C, or any combination thereof. In someaspects, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736. Inother aspects, the immune checkpoint inhibitor is an inhibitor ofCTLA-4, for example, and anti-CTLA-4 antibody. In some aspects, theanti-CTLA-4 antibody is ipilimumab.

In other methods wherein the disease to be treated is cancer or anotherproliferative disease, the compounds of the disclosure, as well aspharmaceutical compositions comprising them, can be administered incombination with an alkylating agent (e.g, cyclophosphamide (CY),melphalan (MEL), and bendamustine), a proteasome inhibitor agent (e.g.,carfilzomib), a corticosteroid agent (e.g, dexamethasone (DEX)), or animmunomodulatory agent (e.g., lenalidomide (LEN) or pomalidomide (POM)),or any combination thereof.

In some embodiments, the disease to be treated is an autoimmunecondition or an inflammatory condition. In these aspects, the compoundsof the disclosure, as well as pharmaceutical compositions comprisingthem, can be administered in combination with a corticosteroid agentsuch as, for example, triamcinolone, dexamethasone, fluocinolone,cortisone, prednisolone, or flumetholone, or any combination thereof.

In other methods wherein the disease to be treated is an autoimmunecondition or an inflammatory condition, the compounds of the disclosure,as well as pharmaceutical compositions comprising them, can beadministered in combination with an immune suppressant agent such as,for example, fluocinolone acetonide (RETISERT™), rimexolone (AL-2178,VEXOL™, ALCO™), or cyclosporine (RESTASIS™), or any combination thereof.

In some embodiments, the disease to be treated is beta-thalassemia orsickle cell disease. In these aspects, the compounds of the disclosure,as well as pharmaceutical compositions comprising them, can beadministered in combination with one or more agents such as, forexample, HYDREA™ (hydroxyurea).

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples moleculeswith a single chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers may be obtained by methods known to thoseskilled in the art.

Compounds of the disclosure can be prepared, for example, by referenceto the following schemes.

In some aspects, the compounds of the disclosure include syntheticintermediates useful in the preparation of other compounds of thedisclosure. In this regard, the compounds of the disclosure include, forexample, the compounds of formula SI-1, formula SI-2, formula SI-3, andformula SI-4:

wherein

-   -   aryl is substituted or unsubstituted phenyl;    -   X is a halogen selected from fluorine, chlorine, or bromine; and    -   PG1 is a hydroxyl protecting group;    -   PG2 is a hydroxyl protecting group; or PG1 and PG2, together        with the atoms to which they are attached, form a cyclic        1,2-dihydroxyl protecting group.

In some embodiments of the compounds of formula SI-1, SI-2, SI-3, andSI-4, the aryl is -4-chlorophenyl, 4-chloro-2-(hydroxymethyl)phenyl,-3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro-4-chlorophenyl,3-methyl-4-chlorophenyl, 3-fluoro-4-trifluoromethylphenyl,4-trifluoromethylphenyl, 4-(trifluoromethoxy)phenyl,4-fluoro-3-trifluoromethylphenyl, benzo[d][1,3]dioxazole,4-isopropylphenyl, or -3-chloro-4-fluorophenyl.

In some embodiments of the compounds of formula SI-1 and SI-2, X ischlorine. In other embodiments, X is fluorine. In yet other embodiments,X is bromine.

In some embodiments of the compounds of formula SI-1, SI-2, SI-3, andSI-4, PG1 and PG2 are each a hydroxyl protecting group, oralternatively, PG1 and PG2, together with the atoms to which they areattached, form a cyclic 1,2-dihydroxyl protecting group.

In some embodiments of the compounds of formula SI-1, SI-2, SI-3, andSI-4, PG1 and PG2 are each a hydroxyl protecting group. In otherembodiments, PG1 and PG2, together with the atoms to which they areattached, form a cyclic 1,2-dihydroxyl protecting group. Suitableprotecting groups are well known to those skilled in the art. See, e.g.,Wuts, Peter GM, and Theodora W. Greene. Greene's protective groups inorganic synthesis. John Wiley & Sons, 2006. In some embodiments PG1 andPG2 together form a ketal. In other embodiments PG1 and PG2 togetherform a di-alkyl acetal. In some embodiments, PG1 and PG2 together forman acetonide protecting group, and the compounds have the formula SI-1a,SI-2a, SI-3a, and SI-4a:

Specific embodiments of compounds of formula SI-1, SI-2, SI-3, and SI-4are described in the Experimental Procedures section set forth below.

Compounds of the disclosure include, for example, the compoundsidentified in Table A.

TABLE A Ex. # Structures MW Name  1

422.445  (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((2- aminoquinolin-7-yl)oxy)methyl)-3-methyltetrahydrofuran-3,4-diol  2

476.41621 (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((2- aminoquinolin-7-yl)oxy)methyl)-3-(trifluoromethyl)tetrahydrofuran-3,4-diol  3

432.44   (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((2- aminoquinolin-7-yl)oxy)methyl)-3-ethynyltetrahydrofuran-3,4-diol  4

434.456  (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((2- aminoquinolin-7-yl)oxy)methyl)-3-vinyltetrahydrofuran-3,4-diol  5

436.472  (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-2- (((2-(methylamino)quinalin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol  6

440.435  (2R,3S,4R,5R)-5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((2- aminoquinolin-7-yl)oxy)methyl)-3-methyltetrahydrofuran-3,4-diol  7

448.483  (2R,3S,4R,5R)-5-(4-amino-5-vinyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((2- aminoquinolin-7-yl)oxy)methyl)-3-methyltetrahydrofuran-3,4-diol  8

446.467  (2R,3S,4R,5R)-5-(4-amino-5-ethynyl-7H-pyrrolo[2,3-cl]pyrimidin-7-yl)-2-(((2- aminoquinolin-7-yl)oxy)methyl)-3-methyltetrahydrofuran-3,4-diol  9

441.872  (2R,3S,4R,5R)-2-(((2-aminoquinolin-7-yl)oxy)methyl)-5-(4-chloro-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyltetrahydrofuran-3,4-diol 10

421.457  (2R,3S,4R,5R)-2-(((2-aminoquinolin-7-yl)oxy)methyl)-3-methyl-5-(4-methyl-7H- pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol 11

456.887  (2R,3S,4R,5R)-2-(((2-amino-3-chloroquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 3-methyltetrahydrofuran-3,4-diol12

501.341  (2R,3S,4R,5R)-2-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 3-methyltetrahydrofuran-3,4-diol13

440.435  (2R,3S,4R,5R)-2-(((2-amino-3-fluoroquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 3-methyltetrahydrofuran-3,4-diol14

438.506  (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((2- aminoquinolin-7-yl)thio)methyl)-3-methyltetrahydrofuran-3,4-diol 15

421.461  (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((2-aminoquinolin-7-yl)amino)methyl)-3- methyltetrahydrofuran-3,4-diol 16

420.473  (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(2-(2- aminoquinolin-7-yl)ethyl)-3-methyltetrahydrofuran-3,4-diol 17

310.372  (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-2-((methylthio)methyl)tetrahydrofuran-3,4- diol 18

397.45   S-(((2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4- dihydroxy-3-methyltetrahydrofuran-2-yl)methyl)-L-homocysteine 19

294.311  (2R,3S,4R,5R)-5-(4-amino-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methoxymethyl)-3-methyltetrahydrofuran- 3,4-diol 20

356.382  (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-2-(phenoxymethyl)tetrahydrofuran-3,4-diol 21

414.422  1-(3-(((2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4- dihydroxy-3-methyltetrahydrofuran-2-yl)methoxy)phenyl)urea 22

385.424  (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((3- (aminomethyl)phenoxy)methyl)-3-methyltetrahydrofuran-3,4-diol 23

298.727  (2S,3S,4R,5R)-5-(4-amino-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-(chloromethyl)-3-methyltetrahydrofuran- 3,4-diol 24

395.419  (2R,3S,4R,5R)-2-(((1H-indol-6- yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3- methyltetrahydrofuran-3,4-diol 25

396.407  (2R,3S,4R,5R)-2-(((1H-indazol-6- yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3- methyltetrahydrofuran-3,4-diol 26

390.824  (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(4-chlorophenyl)(hydroxy)methyl)-3- methyltetrahydrofuran-3,4-diol 27

392.815  (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(4- chlorophenyl)fluoromethyl)-3-methyltetrahydrofuran-3,4-diol 28

419.866  (2R,3S,4R,5R)-2-((R)-(4-chlorophenyl)(hydroxy)methyl)-3-methyl-5-(4-(2-methylhydrazineylidene)-1,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-3,4-diol 29

437.856  (2R,3S,4R,5R)-2-((R)-(4-chloro-3-fluorophenyl)(hydroxy)methyl)-3-methyl-5-(4-(2-methylhydrazineylidene)-1,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-3,4-diol 30

433.893  (2R,3S,4R,5R)-2-((R)-(4-chloro-3-methylphenyl)(hydroxy)methyl)-3-methyl-5-(-4-(2-methylhydrazineylidene)-1,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-3,4-diol 31

454.308  (2R,3S,4R,5R)-2-((R)-(3,4- dichlorophenyl)(hydroxy)methyl)-3-methyl-5-(4-(2-methylhydrazineylidene)-1,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)tetrahydrofuran-3,4-diol 32

452.471  7-((2R,3R,4S,5R)-5-(((2-aminoquinolin-7-yl)oxy)methyl)-3,4-dihydroxy-4- methyltetrahydrofuran-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one O- methyl oxime 33

420.85   7-((2R,3R,4S,5R)-5-((R)-(4- chlorophenyl)(hydroxy)methyl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)-1,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin- 4-one O-methyl oxime 34

438.840  7-((2R,3R,4S,5R)-5-((R)-(4-chloro-3-fluorophenyl)(hydroxy)methyl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)-1,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin- 4-one O-methyl oxime 35

434.877  7-((2R,3R,4S,5R)-5-((R)-(4-chloro-3-methylphenyl)(hydroxy)methyl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)-1,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin- 4-one O-methyl oxime 36

472.397  7-((2R,3R,4S,5R)-5-((R)-(3-fluoro-4-trifluoromethyl)phenyl)(hydroxy)methyl)-3,4-dihydroxy-4-methyltetrahydrofuran-2- yl)-1,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one O-methyl oxime 37

455.292  7-((2R,3R,4S,5R)-5-((R)-(3,4-dichlorophenyl)(hydroxy)methyl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)-1,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin- 4-one O-methyl oxime 38

434.877  7-((2R,3R,4S,5R)-5-((R)-(4- chlorophenyl)(hydroxy)methyl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)-1,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin- 4-one O-ethyl oxime 39

461.903  3-(7-((2R,3R,4S,5R)-5-((R)-(4-chlorophenyl)(hydroxy)methyl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,1- dimethylurea 40

324.399  (2S,3S,4R,5R)-3-methyl-5-(4- methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- ((methylthio)methyl)tetrahydrofuran-3,4- diol 41

433.85   1-(3-(((2R,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4- dihydroxy-3-methyltetrahydrofuran-2-yl)methoxy)phenyl)urea 42

417.85   (2S,3S,4R,5R)-N-(3- aminomethyl)phenyl)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4- dihydroxy-3-methyltetrahydrofuran-2-carboxamide 43

398.42   (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-(3-(aminomethyl)phenyl)-3,4-dihydroxy-3-methyltetrahydrofuran-2-carboxamide 44

420.85   (Z)-7-((2R,3R,4S,5R)-5-((R)-(4-chlorophenyl)(hydroxy)methyl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin- 4-one O-methyl oxime 45

482.49   (Z)-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(((2-(methoxyamino)quinolin-7- yl)oxy)methyl)-4-methyltetrahydrofuran-2-yl)-3,7-dihydro-4H-pyrrolo[2,3- d]pyrimidin-4-one O-methyl oxime 46

406.82   (Z)-7-((2R,3R,4S,5R)-5-((R)-(4-chlorophenyl)(hydroxy)methyl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin- 4-one oxime 47

425.27   (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(3,4-dichlorophenyl)(hydroxy)methyl)-3- methyltetrahydrofuran-3,4-diol 48

(2R,3S,4R,5R)-5-(4-amino-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(3,4-dichlorophenyl)(hydroxy)methyl)-3- methyltetrahydrofuran-3,4-diolSulfate Salt 49

384.39   (2R,3S,4R,5R)-5-(4-amino-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2-(benzo[d][1,3]dioxol-5-ylmethyl)-3- methyltetrahydrofuran-3,4-diol 50

409.27   (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(3,4-dichlorobenzyl)-3-methyltetrahydrofuran- 3,4-diol 51

394.25   (2R,3S,4R,5R)-2-(3,4-dichlorobenzyl)-3-methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-3,4-diol 52

369.37   (2R,3S,4R,5R)-2-(benzo[d][1,3]dioxol-5-ylmethyl)-3-methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)telsahydrofuran-3,4-diol 53

407.42   (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-2- ((quinolin-7-yloxy)methyl)tetrahydrofuran-3,4-diol 54

406.43   (2R,3S,4R,5R)-3-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((quinolin-7-yloxy)methy)tetrahydrofuran- 3,4-diol 55

500.35   (2R,3S,4R,5R)-2-(((2-amino-3- bromoquinolin-7-yl)oxy)methyl)-3-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol 56

404.85   (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(4-chloro-3-methylphenyl)(hydroxy)methyl)- 3-methyltetrahydrofuran-3,4-diol57

403.86   (2R,3S,4R,5R)-2-((R)-(4-chloro-3-methylphenyl)(hydroxy)methyl)-3-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)tetrahydrofuran-3,4-diol 58

424.28   (2R,3S,4R,5R)-2-((R)-(3,4- dichlorophenyl)(hydroxy)methyl)-3-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol 59

397.47   (2R,3S,4R,5R)-2-((R)-hydroxy(4-isopropylphenyl)methyl)-3-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-3,4-diol 60

439.39   (2R,3S,4R,5R)-2-((R)-hydroxy(4-(trifluoromethoxy)phenyl)methyl)-3- methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol 61

441.38   (2R,3S,4R,5R)-2-((R)-(4-fluoro-3-(trifluoromethyl)phenyl)(hydroxy)methyl)-3-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol 62

423.39   (2R,3S,4R,5R)-2-((R)-hydroxy(4-trifluoromethyl)phenyl)methyl)-3-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)tetrahydrofuran-3,4-diol 63

442.37   (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(4- fluoro-3-(trifluoromethyl)phenyl)(hydroxy)methyl)-3-methyltetrahydrofuran-3,4-diol 64

403.86   (2R,3S,4R,5R)-2-(4-chloro-2-(hydroxymethyl)benzyl)-3-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-3,4-diol 65

404.85   (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-c]pyrimidin-7-yl)-2-(4-chloro- 2-(hydroxymethyl)benzyl)-3-methyltetrahydrofuran-3,4-diol 66

425.27   (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((S)-(3,4-dichlorophenyl)(hydroxy)methyl)-3- methyltetrahydrofuran-3,4-diol 67

409.45   (2R,3S,4R,5R)-3-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((3- methylimidazo[1,2-a]pyridin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol 68

410.43   (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-2-(((3-methylimidazo[1,2-a]pyridin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol 69

458.82   (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(4-chloro-3-methylphenyl)(hydroxy)methyl)-3-(trifluoromethyl)tetrahydrofuran-3,4- diol 70

462.79   (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(4-chloro-3-fluorophenyl)(hydroxy)methyl)-3-(trifluoromethyl)tetrahydrofuran-3,4- diol 71

496.34   (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(3- fluoro-4-(trifluoromethyl)phenyl)(hydroxy)methyl)-3-(trifluoromethyl)tetrahydrofuran-3,4- diol 72

446.33   (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[23-d]pyrimidin-7-yl)-2-((R)-(3,4-difluorophenyl)(hydroxy)methyl)-3-(trifluoromethyl)tetrahydrofuran-3,4-diol 73

441.27   (2R,3S,4R,5R)-2-((R)-(3,4-dichlorophenyl)(hydroxy)methyl)-5-(4- (hydroxyamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3- methyltetrahydrofuran-3,4-diol 74

403.87   (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(2- (aminomethyl)-4-chlorobenzyl)-3-methyltetrahydrofuran-3,4-diol 75

417.89   (2R,3S,4R,SR)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(4-chloro-2-((methylamino)methyl)benzyl)-3- methyltetrahydrofuran-3,4-diol

EXPERIMENTAL PROCEDURES Synthesis of Intermediates Synthesis of Int-1

Step 1. Synthesis of((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methylbenzoate (Int-1-2)

To a mixture of compound Int-1-1 (40.00 g, 210.31 mmol, 1 eq.) in DCM(400 mL) was added dropwise TEA (63.84 g, 630.94 mmol, 87.82 mL, 3 eq.)at 0° C. under N₂. BzCl (32.52 g, 231.34 mmol, 26.88 mL, 1.1 eq.) wasadded dropwise to the mixture at 0° C. under N₂. The mixture was stirredat 0° C. for 1 h under N₂. The mixture was combined another reactionmixture with 10 g of Int-1-1. The combined mixture was quenched by water(600 mL). The organic layer was separated. The aqueous was extractedwith DCM (300 mL×3). The combined organic layers were washed withsaturated NaHCO₃solution (400 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=50/1 to 2/1) to give compound 2 (67.00 g,227.66 mmol, 86.60% yield) as a yellow solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ=8.12-7.95 (m, 2H), 7.66-7.53 (m, 1H), 7.51-7.41 (m, 2H),5.97 (d, J=3.7 Hz, 1H), 4.87-4.75 (m, 1H), 4.60 (d, J=3.5 Hz, 1H),4.47-4.35 (m, 2H), 4.19 (dd, J=2.2, 4.0 Hz, 1H), 3.27 (d, J=4.0 Hz, 1H),1.52 (s, 3H), 1.33 (s, 3H).

Step 2. Synthesis of((3aR,5R,6aS)-2,2-dimethyl-6-oxotetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methylbenzoate (Int-1)

Two batches in parallel: To a mixture of compound Int-1-2 (10.00 g,33.98 mmol, 1 eq.) in DCM (100 mL) was added DMP (43.24 g, 101.94 mmol,31.56 mL, 3 eq.) at 0° C. The mixture was stirred at 15° C. for 4 h. Themixture was filtered and the filtrate was concentrated. The residue wasdiluted with EtOAc (500 mL) and the mixture was filtered. The filtratedwas diluted with saturated NaHCO₃ (300 mL). The mixture was extractedwith EtOAc (200 mL*3). The combined organic layers were washed withbrine (300 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=20/1 to 3/1) to give Int-1 (17.00 g, 58.16 mmol,85.59% yield) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d)δ=8.00-7.91 (m, 2H), 7.65-7.53 (m, 1H), 7.50-7.40 (m, 2H), 6.15 (d,J=4.4 Hz, 1H), 4.78-4.67 (m, 2H), 4.54-4.41 (m, 2H), 1.53 (s, 3H), 1.44(s, 3H)

Synthesis of 2-chloroquinoline-7-ol (Int-2)

To a mixture of quinoline-2,7-diol (Int-2-1, 5.00 g, 31.03 mmol, 1 eq.)in DMF (50 mL) was added drop wise thionyl chloride (14.76 g, 124.10mmol, 9.00 mL, 4 eq.) at 0° C. The mixture was stirred at 20° C. for 30min and then stirred at 70° C. for 2 h. The mixture was concentrated toa residue. The residue was diluted with saturated NaHCO₃solution (100mL). The mixture was extracted with EtOAc (30 mL×4). The combinedorganic layers were washed with brine (40 mL), dried over Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=50/1 to 3/1) to givecompound Int-2 (5.30 g, 29.51 mmol, 95.11% yield) as a yellow solid. ¹HNMR (400 MHz, CHLOROFORM-d) δ=8.03 (d, 0.1=8.4 Hz, 1H), 7.73 (d, J=8.8Hz, 1H), 7.34 (d, J=2.3 Hz, 1H), 7.25 (s, 1H), 7.20 (dd, J=2.5, 8.9 Hz,1H), 5.45 (s, 1H).

Synthesis of Int-3

To a mixture of compound Int-3-1 (200 mg, 1.62 mmol, 1 eq.) in THF (6mL) was added Boc₂O (425.32 mg, 1.95 mmol, 447.71 uL, 1.2 eq.) at 25° C.The mixture was stirred at 25° C. for 3 h. LCMS showed compound Int-3-1was consumed and the desired MS was observed. The reaction was quenchedby saturated NaHCO₃solution (10 mL), extracted with EtOAc (5 mL×3). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate=1/0 to 1/1) to give compound Int-3 (180mg, 789.36 umol, 48.61% yield, LCMS purity 97.91%) as colorless oil. ¹HNMR (400 MHz, CHLOROFORM-d) δ=7.20 (t, J=7.8 Hz, 1H), 6.91-6.69 (m, 3H),4.81 (s, 1H), 4.28 (br d, J=5.5 Hz, 2H), 1.47 (s, 9H)

Synthesis of Int-4

A mixture of compound Int-4-1 (14.5 g, 94.42 mmol, 1 eq.) andSelectfluor (50.17 g, 141.63 mmol, 1.5 eq.) was added ACN (725 mL), AcOH(152.25 g, 2.54 mol, 145 mL, 26.85 eq.) and degassed and purged with N₂for 3 times, and then the mixture was stirred at 70° C. for 16 hr underN₂ atmosphere. LCMS showed no compound Int-4-1 was remained. Several newpeaks were shown on LCMS and -45% of desired compound was detected. Thereaction mixture was concentrated under reduced pressure to removesolvent. The residue was diluted with toluene (200 mL) and concentratedunder reduced pressure to remove solvent twice. The residue was purifiedby column chromatography (SiO₂, petroleum ether/ethyl acetate=30/1 to8/1) to give compound Int-4 (10 g, 54.46 mmol, 57.68% yield, LCMS purity93.43%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.49 (br s,1H) 8.55-8.67 (m, 1H) 7.71 (t, J=2.63 Hz, 1H); LCMS: (M+H⁺): 171.9.

Synthesis of Int-5

Step 1. Preparation of 7-bromoquinolin-2-amine (Int-5-2)

To a solution of compound Int-5-1 (6 g, 24.74 mmol, 1 eq.) in NH₃.H₂O(80 mL) and dioxane (80 mL) was stirred at 120° C. for 6 h (50 psi). TLCshowed compound Int-1-1 was remained and one new spot formed. Thereaction was clean according to TLC (Petroleum ether/Ethyl acetate=5:1,R_(f)=0.08). The reaction mixture was concentrated under reducedpressure to remove solvent. The residue was diluted with H₂O (100 mL)and extracted with EtOAc (50 mL×3). The combined organic layers weredried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=50:1 to 1:1). Compound Int-5-2 (3.25 g,14.29 mmol, 57.77% yield, 98.11% purity) was obtained as a yellow solid.LCMS: (M+H⁺): 223.0; TLC (Petroleum ether:Ethyl acetate=5:1) R_(f)=0.08.

Step 2. Preparation of 7-bromo-N-tritylquinolin-2-amine (Int-5-3)

To a solution of compound Int-5-2 (0.2 g, 896.58 umol, 1 eq.) in ACN (10mL) was added TEA (181.45 mg, 1.79 mmol, 249.59 uL, 2 eq.) and TrtCl(299.93 mg, 1.08 mmol, 1.2 eq.) at 25° C. The mixture was stirred at 80°C. for 0.5 h. TLC showed Compound Int-5-2 was remained and one new pointformed (Petroleum ether:Ethyl acetate=3:1, R=0.68). The reaction mixturewas concentrated under reduced pressure to remove solvent. The residuewas diluted with H₂O 15 mL and extracted with DCM (10 mL×3). Thecombined organic layers were washed with brine (20 mL×2), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=1:0 to 5:1) and based on TLC (Petroleumether:Ethyl acetate=3:1, R_(f)=0.68). Compound Int-5-3 (2 g, 3.45 mmol,76.90% yield, 80.22% purity) was obtained as a white solid. TLC(Petroleum ether:Ethyl acetate=3:1) R_(f)=0.68; LCMS: (M+H⁺): 467.0.LCMS purity 80.22%; ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.69 (s, 1H), 7.39(d, J=9.04 Hz, 1H), 7.13-7.35 (m, 15H), 6.46 (s, 1H), 6.15 (d, J=9.04Hz, 1H).

Step 3. Preparation of 2-(tritylamino) quinolin-7-ol (Int-5)

To a solution of compound Int-5-3 (0.6 g, 1.29 mmol, 1 eq.) in dioxane(3 mL) and H₂O (3 mL) was added KOH (289.36 mg, 5.16 mmol, 4 eq.),X-PPHOS (95.48 mg, 193.39 umol, 0.15 eq.) and Pd₂(dba)₃ (118.06 mg,128.93 umol, 0.1 eq.) under N₂ at 25° C. The mixture was stirred at 80°C. for 16 hr. LC-MS showed no compound Int-5-3 was remained. One mainpeak was shown on LC-MS and desired compound was detected. The reactionmixture was filtered, and the solution was concentrated under reducedpressure to remove solvent. The residue was diluted with H₂O 10 mL andextracted with DCM (15 mL×2). The combined organic layers were washedwith brine (10 mL×2), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by prep-TLC(SiO₂, Petroleum ether/Ethyl acetate=1:1, 5% TEA) and based on TLC(Petroleum ether/Ethyl acetate=1:1, R_(f)=0.21, 5% TEA). Compound Int-5(0.23 g, crude) was obtained as a yellow solid. TLC (Petroleumether:Ethyl acetate=1:1, 5% TEA) R_(f)=0.21; LCMS: (M+H⁺): 403.1.

Synthesis of Int-6

To a solution of Mg (979.09 mg, 40.28 mmol, 1.3 eq.) was added compoundInt-6-1 (7 g, 30.99 mmol, 1 eq.) in THF (26 mL) at 40° C. under N₂. Themixture was stirred at 40° C. for 0.5 h. Mg was consumed. Compound Int-6(7.75 g, crude) in THF (26 mL) was used into the next step withoutfurther purification as a yellow liquid.

Synthesis of Int-7

To a mixture of Mg (362.73 mg, 14.92 mmol, 1.5 eq.) and 12 (252.52 mg,994.94 umol, 200.42 uL, 0.1 eq.) was added compound Int-7-1 (2 g, 9.95mmol, 1.19 mL, 1 eq.) in THF (20 mL) at 25° C. under N₂. The mixture wasstirred at 25° C. for 0.5 h. Mg was consumed. Compound Int-7 (2.24 g,crude) in THF (20 mL) was obtained as brown oil which was used for nextstep.

Synthesis of Int-8

A 50 mL RBF with septum containing Mg (34.01 mg, 1.42 mmol) was driedunder high vacuum with a heat gun and cooled under Ar. The flask wascharged with THF (0.40 mL), 2/5 portion of4-Bromo-1-chloro-2-methylbenzene (0.19 mL, 1.34 mmol), and one drop ofDIBAL (1M, toluene). The reaction was stirred at rt but no exotherm wasobserved, which might mean that the magnesium was not initiating.Another drop of DIBAL was added and this time some exotherm took place.After stirring for 10 min, the remaining4-bromo-1-chloro-2-methylbenzene and another THF (0.30 mL) were addedand stirring was continued for 1 h. As all the magnesium dissolved, theGrignard reagent Int-8 was used as it was.

Synthesis of Int-9

To a solution of 3-bromo-2-chloro-7-methoxy-quinoline (Int-9-1,WO2017/032840 A1) (640 mg, 2.35 mmol) in Chloroform (70 mL) was addedBoron tribromide (4.4 mL, 46.97 mmol) at 0° C., the reaction mixture wasstirred at 80° C. overnight. TLC (PE:EA=1:1, R_(f)=0.5) and LCMS showed12% of SM left. The reaction was quenched with MeOH slowly at 0° C., EAwas added and adjusted to pH 8 with aqueous NaHCO₃. The organic phasewas separated and wash with brine. The organic phase was concentratedunder vacuum to give the crude product which was purified by silica gelcolumn chromatography (PE:EA=2:1 to PE:EA=1:1) to give3-bromo-2-chloro-quinolin-7-ol (Int-9) (339 mg, 1.2852 mmol, 54.727%yield) as a white solid. LCMS M+H⁺: 258/260.1/262

Example 1.(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((2-aminoquinolin-7-yl)oxy)methyl)-3-methyltetrahydrofuran-3,4-diol(1)

Step 1. Preparation of((3aR,5R,6R,6aR)-6-hydroxy-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methylbenzoate (I a)

To a mixture of Int-1 (17.00 g, 58.16 mmol, 1 eq.) in THF (200 mL) wasadded dropwise MeMgBr (3 M, 58.16 mL, 3 eq.) at -78° C. under N₂. Themixture was stirred at -78° C. for 1 h under N₂. The combined mixturewas quenched by saturated NH₄Cl (200 mL), extracted with EtOAc (50mL*3). The combined organic layers were washed with brine (100 mL),dried over Na₂SO₄, filtered and concentrated. The crude product waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=15/1 to 5/1) to compound 1a as a white solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ=8.13-8.01 (m, 2H), 7.64-7.51 (m, 1H), 7.48-7.38 (m, 2H),5.83 (d, J=4.0 Hz, 1H), 4.57 (dd, J=3.1, 11.9 Hz, 1H), 4.38 (dd, J=8.2,11.9 Hz, 1H), 4.21-4.06 (m, 2H), 2.71 (s, 1H), 1.60 (s, 3H), 1.37 (s,3H), 1.26 (s, 3H).

Step 2. Preparation of(3aR,5R,6R,6aR)-5-(hydroxymethyl)-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol(1b)

A mixture of compound 1a (2.30 g, 7.46 mmol, 1 eq.) and MeONa (806.00mg, 14.92 mmol, 2 eq.) in MeOH (20 mL) was stirred at 15° C. for 0.5 h.The mixture was quenched by solid NH₄Cl (4 g) and filtered. The filtratewas concentrated. The crude product was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=5/1 to 1/3) to givecompound 1b (1.30 g, 6.37 mmol, 85.34% yield) as a white solid. ¹H NMR(400 MHz, CHLOROFORM-d) δ=5.80 (d, J=4.0 Hz, 1H), 4.13 (d, J=3.7 Hz,1H), 3.96-3.71 (m, 3H), 2.67 (s, 1H), 1.81-1.69 (m, 1H), 1.60 (s, 3H),1.37 (s, 3H), 1.18 (s, 3H)

Step 3. Preparation of(3aR,5R,6R,6aR)-5-(((2-chloroquinolin-7-yl)oxy)methyl)-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol(1c)

To a mixture of PPh₃ (3.50 g, 13.35 mmol, 3 eq.) and DEAD (1.55 g, 8.90mmol, 1.62 mL, 2 eq.) in THF (15 mL) was stirred at 20° C. for 30 minunder N₂. 2-chloroquinolin-7-ol (Int-2, 799.51 mg, 4.45 mmol, 1 eq.) wasadded to the mixture followed by compound 1b (1.00 g, 4.90 mmol, 1.1eq.) at 20° C. The mixture was stirred at 20° C. for 12 h. The mixturewas quenched by water (20 mL), extracted with EtOAc (10 mL×2). Thecombined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 3:1) to givecompound 1c (1.4 g, crude) as a white solid. LCMS: (M+H⁺): 366.1.

Step 4. Preparation of(3R,4S,5R)-5-(((2-chloroquinolin-7-yl)oxy)methyl)-4-methyltetrahydrofuran-2,3,4-triol(1d)

A mixture of compound 1c (900 mg, 2.46 mmol, 1 eq.) in TFA (10 mL) andH₂O (1 mL) was stirred at 20° C. for 0.5 h. The mixture was concentratedand the residue was dissolved into EtOAc (15 mL). SaturatedNaHCO₃solution (30 mL) was added to the mixture, and the organic layerwas separated. The mixture was extracted with EtOAc (15 mL×4). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=3/1 to 0/1) to give compound 1d (280 mg,845.67 umol, 34.37% yield, 98.38% purity) as a white solid. ¹H NMR (400MHz, METHANOL-d4) 5=8.26 (d, J=8.6 Hz, 1H), 7.88 (d, J=9.3 Hz, 1H),7.45-7.25 (m, 3H), 5.39-5.20 (m, 1H), 4.59 (s, 1H), 4.40 (dd, J=3.4, 5.6Hz, 1H), 4.35-4.07 (m, 3H), 3.86 (d, J=4.4 Hz, 1H), 3.68 (d, J=3.5 Hz,1H), 1.37 (d, J=17.5 Hz, 3H).

Step 5. Preparation of(2R,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((2-chloroquinolin-7-yl)oxy)methyl)-3-methyltetrahydrofuran-3,4-diol(1e)

To a mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (127.29 mg, 828.87umol, 1 eq.) in THF (10 mL) was added pyridine (65.56 mg, 828.87 umol,66.90 uL, 1 eq.) at 25° C. DIAD (335.21 mg, 1.66 mmol, 322.32 uL, 2 eq.)was added followed by tributylphosphane (335.39 mg, 1.66 mmol, 409.01uL, 2 eq.) at 25° C. under N₂. Compound 1d was added at 25° C. under N₂.The mixture was stirred at 25° C. for 12 h under N₂. The mixture wasconcentrated. The residue was dissolved in EtOAc (50 mL). Water (100 mL)was added to the mixture. The organic layer was separated. The mixturewas extracted with EtOAc (50 mL×2). The combined organic layers werewashed with brine (100 mL), dried over Na₂SO₄, and concentrated. Theresidue was purified by prep-TLC (SiO₂, Petroleum ether/Ethylacetate=1/3) to give compound 1e (130 mg, crude) as a white solid. LCMS:(M+H⁺): 462.9.

Step 6. Preparation of(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((2-aminoquinolin-7-yl)oxy)methyl)-3-methyltetrahydrofuran-3,4-diol(1)

A mixture of compound 1e (80 mg, 173.42 umol, 1 eq.) and NH. H₂O (36.40g, 259.66 mmol, 40.00 mL, 1497.27 eq.) in dioxane (2 mL) was stirred at145° C. for 48 h. The mixture was concentrated. The residue was purifiedby prep-HPLC ([water(10 mM NH₄HCO₃)-ACN]; B %: 20%-50%) to give compound1 (9.13 mg, 21.33 umol, 12.30% yield, 98.71% purity) as a light yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ=8.07 (s, 1H), 7.80 (d, J=8.8 Hz, 1H),7.55 (d, J=8.8 Hz, 1H), 7.41 (d, J=3.7 Hz, 1H), 7.04-6.92 (m, 3H), 6.87(dd, J=2.4, 8.7 Hz, 1H), 6.64-6.57 (m, 2H), 6.33 (s, 2H), 6.17 (d, J=7.9Hz, 1H), 5.37 (d, J=7.2 Hz, 1H), 5.00 (s, 1H), 4.42 (t, J=7.5 Hz, 1H),4.27-4.13 (m, 3H), 1.30 (s, 3H); ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ=8.07(s, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.56 (d, J=8.7 Hz, 1H), 7.40 (d, J=3.8Hz, 1H), 6.99-6.84 (m, 2H), 6.67-6.57 (m, 2H), 6.17 (d, J=7.9 Hz, 1H),4.42 (d, J=7.9 Hz, 1H), 4.24-4.12 (m, 3H), 1.30 (s, 3H) LCMS: (M+H⁺):423.1.

Example 2.(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((2-aminoquinolin-7-yl)oxy)methyl)-3-(trifluoromethyl)tetrahydrofuran-3,4-diol(2)

Step 1. Preparation of((3aR,5R,6R,6aR)-6-hydroxy-2,2-dimethyl-6-(trifluoromethyl)tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methyl benzoate (2a)

A mixture of compound Int-1 (4.00 g, 13.69 mmol, 1 eq.) in THF (40 mL)was degassed and purged with N₂ for 3 times, and then the mixture wascooled to 0° C., and then the mixture was added TMSCF₃ (4.09 g, 28.74mmol, 2.1 eq.), TBAF (1 M, 13.69 mL, 1 eq.), then the mixture wasstirred at 0° C. for 1 h under N₂ atmosphere. TLC indicated compoundInt-1 was consumed completely and new spots formed. The reaction wasclean according to TLC. The reaction was quenched by sat. aq. NH₄Cl (10mL), and extracted with EtOAc (10 mL×2), and then the organic phase wasconcentrated in vacuo. Compound 2a (4 g, crude) was obtained as a yellowoil. TLC (Petroleum ether:Ethyl acetate=3:1) R_(f)=0.29.

Step 2. Preparation of(3aR,5R,6R,6aR)-5-(hydroxymethyl)-2,2-dimethyl-6-(trifluoromethyl)tetrahydrofuro[2,3-d][1,3]dioxol-6-ol(2b)

To a solution of compound 2a (4.00 g, 11.04 mmol, 1 eq.) in MeOH (20 mL)was added NaOMe (1.19 g, 22.08 mmol, 2 eq.). The mixture was stirred at25° C. for 0.5 h. TLC indicated compound 2a was consumed completely andnew spots formed. The reaction was clean according to TLC. The reactionwas quenched by NH₄Cl (20 g), and filtered, the filtrate wasconcentrated in vacuo. The residue was purified by column chromatography(SiO₂, Petroleum ether/Ethyl acetate=4/1 to 0:1). Compound 2b (2.6 g,crude) was obtained as a white solid. TLC (Petroleum ether:Ethylacetate=3:1) R_(f)=0.07.

Step 3. Preparation of(3aR,5R,6R,6aR)-5-(((2-chloroquinolin-7-yl)oxy)methyl)-2,2-dimethyl-6-(trifluoromethyl)tetrahydrofuro[2,3-d][1,3]dioxol-6-ol(2c)

A mixture of PPh₃ (5.28 g, 20.14 mmol, 2 eq.) in THF (20 mL) wasdegassed and purged with N₂ for 3 times, and then the mixture was cooledto 0° C., then the mixture was added DEAD (3.51 g, 20.14 mmol, 3.66 mL,2 eq.) stirred at 0° C. for 30 min, then compound 2b (2.6 g, 10.07 mmol,1 eq.) and 2-chloroquinolin-7-ol (2.17 g, 12.08 mmol, 1.2 eq.) was addedat 0° C., the mixture was stirred at 25° C. for 12 h under N₂atmosphere. LC-MS showed compound 2b was consumed completely and onemain peak with desired mass was detected. TLC indicated compound 2b wasconsumed completely and new spots formed. The reaction was cleanaccording to TLC. The mixture was concentrated in vacuo. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=4/1 to 1:1). Compound 2c (1.5 g, crude) was obtained as a yellowoil. LCMS: (M+H⁺): 420.0; TLC (Petroleum ether:Ethyl acetate=3:1)R_(f)=0.36.

Step 4. Preparation of(3R,4S,5R)-5-(((2-chloroquinolin-7-yl)oxy)methyl)-4-(trifluoromethyl)tetrahydrofuran-2,3,4-triol(2d)

To compound 2c (1.50 g, 3.57 mmol, 1 eq.) was added TFA (452.71 mg, 3.57mmol, 293.97 uL, 90% purity, 1 eq.), the mixture was stirred at 25° C.for 20 min. TLC indicated compound 2c was consumed completely and newspots formed. The reaction was clean according to TLC. The reaction wasquenched by sat. NaHCO₃ (30 mL) and then extracted with EtOAc (10 mL×2).The combined organic phase was washed with brine (10 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude productcompound 2d (1 g, crude) was used into the next step without furtherpurification as a yellow oil. TLC (Petroleum ether:Ethyl acetate=1:1)R_(f)=0.24.

Step 5. Preparation of(2R,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((2-chloroquinolin-7-yl)oxy)methyl)-3-(trifluoromethyl)tetrahydrofuran-3,4-diol(2e)

A solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (161.77 mg, 1.05mmol, 1 eq.) in THF (10 mL) was added pyridine (83.33 mg, 1.05 mmol,85.03 uL, 1 eq.), DIAD (426.02 mg, 2.11 mmol, 409.64 uL, 2 eq.),tributylphosphane (426.26 mg, 2.11 mmol, 519.83 uL, 2 eq.), compound 2d(400 mg, 1.05 mmol, 1 eq.) all at once, the mixture was stirred at 25°C. for 12 h under N₂ LC-MS showed compound 2d was consumed completelyand one main peak with desired mass was detected. The mixture wasconcentrated in vacuo. The residue was dissolved in H₂O (10 mL), andthen extracted with EtOAc (10 mL×3), the organic phase was concentratedin vacuo. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=10/1 to 4:1). Compound 2e (300 mg, crude)was obtained as a white solid. TLC (Petroleum ether:Ethyl acetate=1:1)R_(f)=0.58.

Step 6. Preparation of(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((2-aminoquinolin-7-yl)oxy)methyl)-3-(trifluoromethyl)tetrahydrofuran-3,4-diol(2)

To a solution of compound 2e (300 mg, 582.22 umol, 1 eq.) in dioxane (3mL) was added NH₃.H₂O (19.98 g, 142.50 mmol, 21.95 mL, 25% purity,244.75 eq.), the mixture was stirred at 145° C. for 12 h. LC-MS showedcompound 2e was consumed completely and one main peak with desired MSwas detected. The mixture was concentrated in vacuo. The residue waspurified by prep-HPLC (basic condition, HPLC: column: Waters XbridgePrep OBD C18 150*30 10 u; mobile phase: [water (0.04% NH₃H2O)-ACN]; B %:10%-40%, 10 min). Compound 3 (15.73 mg, 32.58 umol, 5.60% yield, and98.67% LCMS purity) was obtained as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ=8.08 (s, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H),7.44 (d, J=3.5 Hz, 1H), 7.08 (br s, 2H), 6.86 (d, J=2.4 Hz, 1H),6.82-6.76 (m, 2H), 6.65 (d, J=3.5 Hz, 1H), 6.59 (d, J=8.8 Hz, 1H), 6.35(s, 2H), 6.21 (d, J=7.3 Hz, 1H), 6.15 (d, J=7.7 Hz, 1H), 4.99 (t, J=7.5Hz, 1H), 4.41-4.25 (m, 3H); ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ=8.05 (s,1H), 7.77 (d, J=8.8 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.41 (d, J=3.5 Hz,1H), 6.84 (d, J=2.2 Hz, 1H), 6.78 (dd, J=2.5, 8.7 Hz, 1H), 6.63 (d,J=3.7 Hz, 1H), 6.58 (d, J=8.8 Hz, 1H), 6.12 (d, J=7.9 Hz, 1H), 4.97 (d,J=7.7 Hz, 1H), 4.39-4.22 (m, 3H); LCMS: (M+H⁺): 477.1; HPLC purity:100.0%.

Example 3.(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((2-aminoquinolin-7-yl)oxy)methyl)-3-ethynyltetrahydrofuran-3,4-diol(3)

Step 1. Preparation of((3aR,5R,6R,6aR)-6-ethynyl-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methylbenzoate (3a)

A mixture of compound Int-1 (4.00 g, 13.69 mmol, 1 eq.) in THF (40 mL)was degassed and purged with N₂ for 3 times, and then the mixture wascooled to 0° C., and then the mixture was added bromo(ethynyl)magnesium(0.5 M, 41.06 mL, 1.5 eq.), then the mixture was stirred at 0° C. for 3h under N₂ atmosphere. TLC indicated compound Int-1 was consumedcompletely and one new spot formed. The reaction was clean according toTLC. The reaction was quenched by sat. aq. NH₄Cl (4 mL) and extractedwith EtOAc (5 mL×3). The organic phase was concentrated in vacuo.Compound 3a (4 g, crude) was obtained as a yellow oil. TLC (Petroleumether:Ethyl acetate=2:1) R_(f)=0.43.

Step 2. Preparation of(3aR,5R,6R,6aR)-6-ethynyl-5-(hydroxymethyl)-2,2-dimethyl tetrahydrofuro[2,3-d][1,3]dioxol-6-ol (3b)

To a solution of compound 3a (4.00 g, 12.57 mmol, 1 eq.) in MeOH (30 mL)was added NaOMe (1.36 g, 25.13 mmol, 2 eq.). The mixture was stirred at25° C. for 0.5 h. TLC indicated compound 3a was consumed completely andnew spots formed. The reaction was clean according to TLC. The reactionwas quenched by NH₄Cl (20 g), and then filtered, and the filtrate wasconcentrated in vacuo at 25° C. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=4/1 to 1:1).Compound 3b (2.6 g. crude) was obtained as a white solid. TLC (Petroleumether:Ethyl acetate=1:1) R_(f)=0.24.

Step 3. Preparation of(3aR,5R,6R,6aR)-5-(((2-chloroquinolin-7-yl)oxy)methyl)-6-ethynyl-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol(3c)

A mixture of PPh₃ (6.37 g, 24.27 mmol, 2 eq.) in THF (20 mL) wasdegassed and purged with N₂ for 3 times, and then the mixture was cooledto 0° C., and then the mixture was added DEAD (4.23 g, 24.27 mmol, 4.41mL, 2 eq.), the mixture was stirred at 0° C. for 30 min, then themixture was added 2-chloroquinolin-7-ol (2.62 g, 14.56 mmol, 1.2 eq.),then the mixture was added compound 3b (2.60 g, 12.14 mmol, 1 eq.) at 0°C., then the mixture was stirred at 25° C. for 12 h under N₂ atmosphere.TLC indicated compound 3b was consumed completely and new spots formed.The reaction was clean according to TLC. The reaction was concentratedin vacuo at 25° C. The residue was purified by column chromatography(SiO₂, Petroleum ether/Ethyl acetate=4/1 to 4:1). Compound 3c (2.4 g,crude) was obtained as a white solid. TLC (Petroleum ether:Ethylacetate=3:1) R_(f)=0.62.

Step 4. Preparation of(3R,4S,5R)-5-(((2-chloroquinolin-7-yl)oxy)methyl)-4-ethynyltetrahydrofuran-2,3,4-triol(3d)

To a solution of compound 3c (2.40 g, 6.39 mmol, 1 eq.) was added TFA(809.08 mg, 6.39 mmol, 525.38 uL, 90% purity, 1 eq.), the mixture wasstirred at 25° C. for 20 min. TLC indicated compound 3c was consumedcompletely and new spots formed. The reaction was clean according toTLC. The reaction was quenched by sat. NaHCO₃ (30 mL) and then extractedwith EtOAc (10 mL×2). The combined organic phase was washed with brine(10 mL), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude product compound 3d (1.9 g, crude) was used into thenext step without further purification as a yellow oil. TLC (Petroleumether:Ethyl acetate=1:1) R_(f)=0.24.

Step 5. Preparation of(2R,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((2-chloroquinolin-7-yl)oxy)methyl)-3-ethynyltetrahydrofuran-3,4-diol(3e)

A solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (182.96 mg, 1.19mmol, 1 eq.) in THF (10 mL) was added pyridine (94.24 mg, 1.19 mmol,96.16 uL, 1 eq.), DIAD (481.83 mg, 2.38 mmol, 463.29 uL, 2 eq.),tributylphosphane (482.09 mg, 2.38 mmol, 587.91 uL, 2 eq.), compound 3d(400 mg, 1.19 mmol, 1 eq.) all at once, the mixture was stirred at 25°C. for 12 h under N₂ LC-MS showed compound 3d was consumed completelyand one main peak with desired MS was detected. The mixture wasconcentrated in vacuo. The residue was dissolved in H₂O (10 mL), andthen extracted with EtOAc (10 mL*3), the organic phase was concentratedin vacuo. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=10/1 to 4:1). Compound 3e (300 mg, crude)was obtained as a white solid. TLC (Petroleum ether:Ethyl acetate=2:1)R_(f)=0.12; LCMS: (M+H⁺): 473.0.

Step 6. Preparation of(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((2-aminoquinolin-7-yl)oxy)methyl)-3-ethynyltetrahydrofuran-3,4-diol(3)

To a solution of compound 3e (300 mg, 636.55 umol, 1 eq.) in dioxane (3mL) was added NH₃.H₂O (5.46 g, 155.80 mmol, 6 mL, 244.75 eq.). Themixture was stirred at 145° C. for 12 h. LC-MS showed compound 3e wasconsumed completely and one main peak with desired MS was detected. Themixture was concentrated in vacuo. The residue was purified by prep-HPLC(HCl condition, column: Luna C18 100*30 5 u; mobile phase: [water (0.05%HCl)-ACN]; B %: 1%-20%, 10 min). Compound 3 (3.32 mg, 6.30 umol, 0.99%yield, 95.96% LCMS purity, 2HCl) was obtained as a white gum. ¹H NMR(400 MHz, DMSO-d₆) δ=8.42 (s, 1H), 8.28 (d, J=9.3 Hz, 1H), 7.86 (d,J=8.6 Hz, 1H), 7.70 (d, J=3.5 Hz, 1H), 7.34 (s, 1H), 7.23-7.16 (m, 2H),7.09 (s, 1H), 7.03 (d, J=3.5 Hz, 1H), 6.92 (d, J=9.5 Hz, 1H), 6.36 (s,1H), 6.15 (d, J=7.7 Hz, 1H), 4.72 (d, J=7.3 Hz, 1H), 4.42-4.35 (m, 2H),3.61 (s, 1H); ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ=8.37 (s, 1H), 8.28 (d,J=9.3 Hz, 1H), 7.85 (d, J=9.5 Hz, 1H), 7.67 (d, J=3.5 Hz, 1H), 7.21-7.16(m, 2H), 6.98 (d, J=3.7 Hz, 1H), 6.89 (d, J=9.0 Hz, 1H), 6.15 (d, J=7.7Hz, 1H), 4.70 (d, J=7.7 Hz, 1H), 4.41-4.35 (m, 3H); LCMS: (M+H⁺): 433.0;HPLC purity: 100.0%.

Example 4.(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((2-aminoquinolin-7-yl)oxy)methyl)-3-vinyltetrahydrofuran-3,4-diol (4)

Step 1. Preparation of((3aR,5R,6R,6aR)-6-hydroxy-2,2-dimethyl-6-vinyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methyl benzoate (4a)

A mixture of compound Int-1 (3.00 g, 10.26 mmol, 1 eq.) in THF (20 mL)was degassed and purged with N₂ for 3 times, and then the mixture wascooled to −78° C., and then the mixture was added bromo(vinyl)magnesium(1 M, 20.53 mL, 2 eq.), then the mixture was stirred at -78° C. for 3 hunder N₂ atmosphere. LC-MS showed compound Int-1 was consumed completelyand one main peak with desired mass was detected. The reaction wasquenched by sat. aq. NH₄Cl (10 mL), and then extracted with EtOAc (10mL×3), and the organic phase was concentrated in vacuo. No purification.Compound 4a (3.29 g, crude) was obtained as a yellow solid. LCMS:(M+H⁺): 319.1.

Step 2. Preparation of(3aR,5R,6R,6aR)-5-(hydroxymethyl)-2,2-dimethyl-6-vinyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol(4b)

To a solution of compound 4a (3.29 g, 10.27 mmol, 1 eq.) in MeOH (30 mL)was added NaOMe (1.11 g, 20.54 mmol, 2 eq.). The mixture was stirred at25° C. for 0.5 h. TLC indicated compound 4a was consumed completely andnew spots formed. The reaction was clean according to TLC. The reactionwas quenched by NH₄Cl (20 g), and filtered, the filtrate wasconcentrated in vacuo. The residue was purified by column chromatography(SiO₂, Petroleum ether: Ethyl acetate=5/1 to 1:1). Compound 4b (1.9 g,crude) was obtained as a white solid. ¹HNMR (400 MHz, CHLOROFORM-d)δ=5.85 (d, J=3.7 Hz, 1H), 5.81-5.71 (m, 1H), 5.53 (dd, J=1.2, 17.2 Hz,1H), 5.30 (dd, J=1.1, 11.0 Hz, 1H), 4.23 (d, J=3.8 Hz, 1H), 4.00 (t,J=5.6 Hz, 1H), 3.69 (d, J=5.7 Hz, 2H), 1.61 (s, 3H), 1.37 (s, 2H),1.40-1.33 (m, 1H).

Step 3. Preparation of(3aR,5R,6R,6aR)-5-(((2-chloroquinolin-7-yl)oxy)methyl)-2,2-dimethyl-6-vinyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol(4c)

A mixture of PPh₃ (4.65 g, 17.74 mmol, 2 eq.) in THF (20 mL) wasdegassed and purged with N₂ for 3 times, and then the mixture was cooledto 0° C., and then the mixture was added DEAD (3.09 g, 17.74 mmol, 3.22mL, 2 eq.), the mixture was stirred at 0° C. for 30 min, then themixture was added 2-chloroquinolin-7-ol (1.91 g, 10.64 mmol, 1.2 eq.),then the mixture was added compound 4b (1.92 g, 8.87 mmol, 1 eq.) at 0°C., then the mixture was stirred at 25° C. for 12 h under N₂ atmosphere.LC-MS showed compound 4b was consumed completely and one main peak withdesired MS was detected. The reaction was concentrated in vacuo at 25°C. The residue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=4/1 to 4:1). Compound 4c (1.2 g, crude) was obtainedas a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.01 (d, J=8.6 Hz,1H), 7.73-7.64 (m, 1H), 7.33 (d, J=2.4 Hz, 1H), 7.27 (d, J=2.6 Hz, 1H),7.26-7.23 (m, 1H), 5.95 (d, J=3.7 Hz, 1H), 5.87-5.76 (m, 1H), 5.70-5.58(m, 1H), 5.38 (dd, J=1.4, 10.9 Hz, 1H), 4.36-4.31 (m, 1H), 4.29 (d,J=4.0 Hz, 1H), 4.17 (dd, J=1.9, 10.7 Hz, 1H), 4.10-4.06 (m, 1H), 1.66(s, 3H), 1.40 (s, 3H); LCMS: (M+H⁺): 378.1.

Step 4. Preparation of(3R,4S,5R)-5-(((2-chloroquinolin-7-yl)oxy)methyl)-4-vinyltetrahydrofuran-2,3,4-triol(4d)

A solution compound 4c of (400 mg, 1.06 mmol, 1 eq.) in TFA (120.72 mg,1.06 mmol, 78.39 uL, 1 eq.), the mixture was stirred at 25° C. for 1 h.LC-MS showed compound 4c was consumed completely and one main peak withdesired mass was detected. The mixture was concentrated in vacuo, andthen dissolved in toluene (10 mL), and then concentrated in vacuo, andrepeated this three times. The crude product compound 4d (400 mg, crude,TFA) was as a yellow oil and used into the next step without furtherpurification. LCMS: (M+H⁺): 338.2.

Step 5. Preparation of(2R,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((2-chloroquinolin-7-yl)oxy)methyl)-3-vinyltetrahydrofuran-3,4-diol(4e)

A solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (136.40 mg, 888.22umol, 1 eq.) in THF (10 mL) was added pyridine (70.26 mg, 888.22 umol,71.69 uL, 1 eq.), DIAD (359.21 mg, 1.78 mmol, 345.39 uL, 2 eq.),tributylphosphane (359.40 mg, 1.78 mmol, 438.30 uL, 2 eq.), compound 4d(300 mg, 888.22 umol, 1 eq.) all at once, the mixture was stirred at 25°C. for 12 h under N₂. LC-MS showed compound 4d was consumed completelyand one main peak with desired MS was detected. The mixture wasconcentrated in vacuo. The residue was dissolved in H2O (10 mL), andthen extracted with EtOAc (10 mL×3), the organic phase was concentratedin vacuo. The residue was purified by prep-TLC (SiO₂, Petroleumether:Ethyl acetate=3:1). Compound 4e (400 mg, crude) was obtained as ayellow oil. TLC (Petroleum ether:Ethyl acetate=3:1) R_(f)=0.37; LCMS:(M+H⁺): 473.0.

Step 6. Preparation of(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((2-aminoquinolin-7-yl)oxy)methyl)-3-vinyltetrahydrofuran-3,4-diol(4)

To a solution of compound 4e (20 mg, 42.26 umol, 1 eq.) in dioxane (3mL) was added NH₃.H₂O (5.46 g, 38.95 mmol, 6 mL, 25%, 921.74 eq.). Themixture was stirred at 145° C. for 12 h. LC-MS showed compound 4e wasconsumed completely and one main peak with desired MS was detected. Themixture was concentrated in vacuo. The residue was purified by prep-HPLC(basic condition; column: YMC-Actus Triart C18 100*30 mm*5 um; mobilephase: [water (10 mM NH₄HCO₃)-ACN]; B %: 15%-35%, 12 min.). Compound 4was got batch 1 (2.7 mg, 98.93%) and batch 2 (9.29 mg, 95%) as a whitesolid. (Batch 1) ¹H NMR (400 MHz, DMSO-d₆) δ=8.07 (s, 1H), 7.80 (br d,J=8.7 Hz, 1H), 7.55 (br d, J=8.6 Hz, 1H), 7.44 (br d, J=3.4 Hz, 1H),7.01 (br s, 2H), 6.93-6.82 (m, 2H), 6.64-6.55 (m, 2H), 6.34 (br s, 2H),6.25 (br d, J=8.1 Hz, 1H), 6.01 (br dd, J=10.6, 17.0 Hz, 1H), 5.61-5.46(m, 2H), 5.28 (br d, J=11.1 Hz, 1H), 5.19 (s, 1H), 4.70 (br t, J=7.5 Hz,1H), 4.20-4.09 (m, 3H); (Batch 1) ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ=8.06(s, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.42 (d, J=3.5Hz, 1H), 6.91-6.86 (m, 2H), 6.63-6.58 (m, 2H), 6.24 (d, J=7.9 Hz, 1H),5.99 (dd, J=10.9, 17.1 Hz, 1H), 5.54 (dd, J=1.7, 17.1 Hz, 1H), 5.30-5.25(m, 1H), 4.70 (d, J=7.9 Hz, 1H), 4.18-4.16 (m, 1H), 4.14-4.08 (m, 1H);(Batch 1) LCMS: (M+H⁺): 435.1; (Batch 1) HPLC purity: 100.0%; (Batch 2)¹H NMR (400 MHz, DMSO-d₆) δ=8.07 (s, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.55(d, J=8.7 Hz, 1H), 7.44 (d, J=3.4 Hz, 1H), 7.01 (br s, 2H), 6.94-6.82(m, 2H), 6.66-6.55 (m, 2H), 6.33 (s, 2H), 6.25 (d, J=7.8 Hz, 1H), 6.01(dd, J=10.7, 17.3 Hz, 1H), 5.60-5.46 (m, 2H), 5.28 (br d, J=12.2 Hz,1H), 5.18 (s, 1H), 4.70 (t, J=7.5 Hz, 1H), 4.21-4.13 (m, 3H), 4.13-4.08(m, 1H); (Batch 2) ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ=8.06 (s, 1H), 7.81(d, J=8.7 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.43 (d, J=3.7 Hz, 1H),6.93-6.83 (m, 2H), 6.64-6.56 (m, 2H), 6.24 (d, J=7.9 Hz, 1H), 5.99 (dd,J=10.8, 17.1 Hz, 1H), 5.57-5.49 (m, 1H), 5.28 (br d, J=11.6 Hz, 1H),4.70 (d, J=8.1 Hz, 1H), 4.20-4.03 (m, 3H); (Batch 2) LCMS: (M+H⁺):435.1; (Batch 2) HPLC purity: 100.0%.

Example 6.(2R,3S,4R,5R)-5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((2-aminoquinolin-7-yl)oxy)methyl)-3-methyltetrahydrofuran-3,4-diol(6)

Step 1. Preparation of((3aR,5R,6R,6aR)-6-hydroxy-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methylbenzoate (6a)

To a mixture of compound Int-4 (94.80 mg, 552.58 umol, 1.2 eq.) in THF(4 mL) was added pyridine (36.42 mg, 460.48 umol, 37.17 uL, 1 eq.) at25° C. DIAD (186.23 mg, 920.97 umol, 179.07 uL, 2 eq.) was addedfollowed by tributylphosphane (186.33 mg, 920.97 umol, 227.23 uL, 2 eq.)at 25° C. under N₂. Compound 1d (150.00 mg, 460.48 umol, 1 eq.) wasadded at 25° C. under N₂. The mixture was stirred at 25° C. for 12 hunder N₂. LCMS showed compound 1d were consumed and the desired MS wasobserved. The mixture was concentrated. The residue was dissolved inEtOAc (50 mL). Water (20 mL) was added to the mixture. The organic layerwas separated. The mixture was extracted with EtOAc (10 mL×3). Thecombined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated. The residue was purified by prep-TLC(SiO₂, petroleum ether/ethyl acetate=1/3) to give compound 6a (100 mg,140.99 umol, 30.62% yield, LCMS purity 67.6%) as a yellow solid. LCMS:(M+H⁺): 479.0.

Step 2. Preparation of(2R,3S,4R,5R)-5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(((2-aminoquinolin-7-yl)oxy)methyl)-3-methyltetrahydrofuran-3,4-diol(6)

A mixture of compound 6a (50 mg, 104.32 umol, 1 eq.) and NH₃.H₂O (3.64g, 25.97 mmol, 4 mL, 248.91 eq.) in dioxane (3 mL) was stirred at 145°C. for 24 h. LCMS showed compound 6a was consumed. The mixture wasconcentrated. The residue was purified by prep-HPLC (column: UniSil120*30*10 um; mobile phase: [water (0.05% HCl)-ACN]; B %: 1%-200%, 11min). Compound 6 (7.24 mg, 15.27 umol, 14.64% yield, LCMS purity 92.88%)was obtained as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ=13.95 (br s,1H), 8.49-8.17 (m, 4H), 7.89 (d, J=8.9 Hz, 1H), 7.60 (s, 1H), 7.27-7.16(m, 2H), 6.93 (d, J=9.3 Hz, 1H), 6.24-6.17 (m, 1H), 4.44-4.11 (m, 5H),1.31 (s, 3H); ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ=8.37-8.27 (m, 2H), 7.89(d, J=8.8 Hz, 1H), 7.59 (s, 1H), 7.29-7.16 (m, 2H), 6.92 (d, J=9.2 Hz,1H), 6.21 (dd, J=1.8, 8.0 Hz, 1H), 4.39-4.21 (m, 4H), 1.30 (s, 3H);LCMS: (M+H⁺): 441.2.

Example 10.(2R,3S,4R,5R)-2-(((2-aminoquinolin-7-yl)oxy)methyl)-3-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(10)

Step 1. Preparation of((3aR,4R,6R,6aR)-2,2,3a-trimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(10a)

To a solution of compound 19a (150 mg, 441.47 umol, 1 eq.) in H₂O (0.3mL) and dioxane (30 mL) was added Cs₂CO₃ (431.52 mg, 1.32 mmol, 3 eq.)and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (2.69 g, 10.73 mmol,3.00 mL, 24.31 eq.) and Pd(dppf)Cl₂ (32.30 mg, 44.15 umol, 0.1 eq.)under N₂. The mixture was stirred at 80° C. for 16 h under N₂. LC-MSshowed no compound 19a was remained. Several new peaks were shown onLC-MS and -58% of desired compound 10a was detected. The reactionmixture was concentrated under reduced pressure to remove solvent. Theresidue was diluted with water 30 mL and extracted with DCM (30 mL×3).The combined organic layers were washed with brine (30 mL×2), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by prep-TLC (SiO₂, Petroleumether/Ethyl acetate=0:1). Compound 10a (70 mg, 219.19 umol, 49.65%yield) was obtained as a yellow oil. ¹H NMR (400 MHz, CHLOROFORM-d)δ=8.69 (s, 1H), 7.21-7.15 (m, 3H), 7.13-7.06 (m, 1H), 6.52 (d, J=3.7 Hz,1H), 6.13 (d, J=3.4 Hz, 1H), 4.78 (d, J=3.4 Hz, 1H), 4.21 (dd, J=3.4,4.8 Hz, 1H), 3.92-3.81 (m, 1H), 3.79-3.69 (m, 1H), 3.47 (br s, 1H), 2.66(s, 3H), 2.28 (s, 1H), 1.64 (s, 3H), 1.57 (s, 3H), 1.38 (s, 3H); TLC(SiO₂, Petroleum ether/Ethyl acetate=0:1): R_(f)=0.45; LCMS: (M+H⁺):320.1.

Step 2. Preparation of7-(((3aR,4R,6R,6aR)-2,2,3a-trimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-N-tritylquinolin-2-amine(10b)

To a mixture of compound 10a (120 mg, 375.76 umol, 1 eq.) and compoundInt-5 (196.61 mg, 488.48 umol, 1.3 eq.) in toluene (3 mL) was added2-(tributyl-phosphanylidene)acetonitrile (181.38 mg, 751.52 umol, 2 eq.)in one portion at 25° C. under N₂. The mixture was stirred at 80° C. for12 h. LC-MS showed no compound 10a was remained. Several new peaks wereshown on LC-MS and 55% of desired compound 10b was detected. Thereaction mixture was concentrated under reduced pressure to removesolvent. The residue was diluted with water 10 mL and extracted withEtOAc 20 mL (10 mL×2). The combined organic layers were washed withbrine 10 mL, dried over Na₂CO₃, filtered and concentrated under reducedpressure to give a residue. The residue was purified by prep-TLC (SiO₂,Petroleum ether/Ethyl acetate=5:1). Compound 10b (100 mg, 133.56 umol,35.54% yield, 94% purity) was obtained as a yellow solid. ¹H NMR (400MHz, CHLOROFORM-d) δ=8.80 (s, 1H), 7.39-7.34 (m, 7H), 7.30-7.22 (m,10H), 6.98 (s, 1H), 6.84 (dd, J=2.2, 8.8 Hz, 1H), 6.58 (d, J=3.5 Hz,1H), 6.44 (br s, 1H), 6.41 (d, J=2.2 Hz, 1H), 6.02 (d, J=8.8 Hz, 1H),4.87 (d, J=2.2 Hz, 1H), 4.54 (dd, J=3.5, 7.0 Hz, 1H), 4.34-4.27 (m, 1H),4.23-4.16 (m, 1H), 2.71 (s, 3H), 1.66 (d, J=11.0 Hz, 6H), 1.44 (s, 3H);LCMS: (M+H⁺): 704.5; TLC (SiO₂, petroleum ether/ethyl acetate=5/1):R_(f)=0.75.

Step 3. Preparation of(2R,3S,4R,5R)-2-(((2-aminoquinolin-7-yl)oxy)methyl)-3-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(10)

To a solution of compound 10b (0.1 g, 142.08 umol, 1 eq.) was added TFA(1.54 g, 12.16 mmol, 1 mL, 90% purity, 85.55 eq.). The mixture wasstirred at 25° C. for 5 min. LC-MS showed no compound 10b was remained.Several new peaks were shown on LC-MS and the desired compound 10 wasdetected. The reaction mixture was concentrated under reduced pressureto remove solvent. The residue was added NH₃.H₂O to adjusted pH around8. The residue was purified by prep-HPLC (basic condition: column:Waters Xbridge 150*25 5 u; mobile phase: [water (0.04% NH₃.H₂O+10 mMNH₄HCO₃)-ACN]; B %: 5%-35%, 10 min). Compound 10 (27.28 mg, 64.54 umol,45.42% yield, 99.70% purity) was obtained as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ=8.66 (s, 1H), 7.80 (dd, J=2.4, 6.4 Hz, 2H), 7.55 (d,J=8.8 Hz, 1H), 6.95 (d, J=2.2 Hz, 1H), 6.87 (dd, J=2.6, 8.8 Hz, 1H),6.78 (d, J=3.9 Hz, 1H), 6.59 (d, J=9.2 Hz, 1H), 6.33 (s, 2H), 6.30 (d,J=8.3 Hz, 1H), 5.46 (br d, J=6.6 Hz, 1H), 5.11 (s, 1H), 4.48 (t, J=7.0Hz, 1H), 4.27-4.16 (m, 2H), 2.64 (s, 3H), 1.31 (s, 3H); ¹H NMR (400 MHz,DMSO-d₆+D₂O) δ=8.64 (s, 1H), 7.82 (d, 1=8.8 Hz, 1H), 7.75 (d, J=3.5 Hz,1H), 7.57 (d, J=8.8 Hz, 1H), 6.96-6.86 (m, 2H), 6.77 (d, J=3.9 Hz, 1H),6.61 (d, J=8.8 Hz, 1H), 6.28 (d, J=7.9 Hz, 1H), 4.47 (d, 0.1=7.9 Hz,1H), 4.24-4.17 (m, 3H), 2.63 (s, 3H), 1.30 (s, 3H); LCMS: (M+H⁺): 422.2;LCMS purity 99.69%; HPLC purity: 100.00%.

Example 12.(2R,3S,4R,5R)-2-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyltetrahydrofuran-3,4-diol(12)

Step 1. Preparation of7-[[(3aR,4R,6R,6aR)-6-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methoxy]-3-bromo-2-chloro-quinoline(12a)

To a solution of[(3aR,4R,6R,6aR)-6-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methanol(19a) (137.5 mg, 0.40 mmol) and 3-bromo-2-chloro-quinolin-7-ol (Int-9)(95.0 mg, 0.37 mmol) in Toluene (5.0 mL),Cyanomethylenetributylphosphorane (0.14 mL, 0.55 mmol) was added at rt.The mixture was stirred at 100° C. for 18 h under N₂. The mixture wasdiluted with DCM (50.0 mL) and washed with brine (20.0 mL×3), dried overNa₂SO₄, filtered and concentrated in vacuum to give crude product whichwas purified by silica gel column chromatography (EA:PE=2:1) to obtain7-[[(3aR,4R,6R,6aR)-6-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methoxy]-3-bromo-2-chloro-quinoline(19a) (38.0 mg, 0.06 mmol, 17.5% yield) as a white solid. LCMS [M+H]:579.0.

Step 2. Preparation of compound 12b

A solution of7-[[(3aR,4R,6R,6aR)-6-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methoxy]-3-bromo-2-chloro-quinoline(12a) (38.0 mg, 0.07 mmol) in 1,4-Dioxane (1.0 mL) and Ammoniumhydroxide (1.5 mL, 39.69 mmol) was stirred at 140° C. for 68 h in aautoclave. LCMS showed the reaction was done and 16.0%, of SM was left.The mixture was concentrated in vacuum to give crude product 12b (37.0mg) which was used in the next step directly. LCMS [M+H]: 541.1.

Step 3. Preparation of(2R,3S,4R,5R)-2-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyltetrahydrofuran-3,4-diol(12)

A solution of7-[[(3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methoxy]-3-bromo-quinolin-2-amine(12b) (37.0 mg, 0.07 mmol) in Water (1.0 mL) and TFA (1.5 mL, 20.19mmol) was stirred at 40° C. for 2 h. LCMS showed the reaction wascompleted, the reaction mixture was purified by prep-HPLC, eluted withMeCN in H2O (0.1% NH.*H₂O) from 10.0% to 95.0% to give(2R,3S,4R,5R)-2-[(2-amino-3-bromo-7-quinolyl)oxymethyl]-5-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-tetrahydrofuran-3,4-diol(Ex. 12) (3.1 mg, 0.0061 mmol, 8.9% yield) as a white solid. LCMS [M+H]:501.1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.29 (s, 1H), 8.06 (s, 1H), 7.60 (d,J=8.8 Hz, 1H), 7.39 (d, J=3.6 Hz, 1H), 6.93-6.99 (m, 4H), 6.55-6.60 (m,3H), 6.16 (d, J=8.0 Hz, 1H), 5.11-5.33 (m, 2H), 4.41 (d, J=7.6 Hz, 1H),4.17-4.25 (m, 3H), 1.30 (s, 3H). ¹H NMR (400 MHz, DMSO-d₆+D₂O) 8.30 (s,1H), 8.07 (s, 1H), 7.62 (d, J=8.4 Hz 1H), 7.39 (d, J=3.6 Hz, 1H),6.95-6.98 (m, 2H), 6.61 (d, J=3.6 Hz, 1H), 6.17 (d, J=8.0 Hz, 1H), 4.42(d, J=8.0 Hz, 1H), 4.19-4.25 (m, 3H), 1.30 (s, 3H).

Example 17.(2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-2-((methylthio)methyl)tetrahydrofuran-3,4-diol(17)

Step 1. Preparation of((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylbenzoate (17a)

To a solution of compound 1a (1 g, 2.48 mmol, 1 eq.) in2,2-dimethoxypropane (12.75 g, 122.42 mmol, 15 mL, 49.44 eq.) was addedTsOH.H₂O (141.31 mg, 742.91 umol, 0.3 eq.). The mixture was stirred at25° C. for 12 hr. LC-MS showed compound 1a was remained. Several newpeaks were shown on LC-MS and desired compound was detected. Thereaction was stirred at 60° C. for 2 hr. TLC indicated compound 1a wasconsumed completely and new spots formed. The reaction was cleanaccording to TLC. The reaction was quenched by NaHCO₃ (20 mL), andextracted with EtOAc (10 mL*3). The organic was concentrated in vacuo.The residue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=5/1 to 4:1). Compound 17a (730 mg, crude) wasobtained as a yellow oil. TLC (Petroleum ether:Ethyl acetate=1:1)R_(f)=0.79.

Step 2. Preparation of((3aR,4R,6R,6aR)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(17b)

To a solution of compound 17a (200 mg, 450.57 umol, 1 eq.) in THF (2 mL)was added NH₃.H₂O (7.28 g, 51.93 mmol, 8.00 mL, 25% purity, 115.26 eq.).The mixture was stirred at 100° C. for 12 hr in a sealed tube. TLCindicated compound 17a was consumed completely and new spots formed. Thereaction was clean according to TLC. The mixture was concentrated invacuo. The residue was purified by prep-TLC (SiO₂, Petroleum ether:Ethylacetate=0:1). Compound 17b (140 mg, crude) was obtained as a whitesolid. TLC (Petroleum ether:Ethyl acetate=0:1) R_(f)=0.14.

Step 3. Preparation ofS-(((3aS,4S,6R,6aR)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)ethanethioate (17c)

A solution of PPh₃ (229.26 mg, 874.06 umol, 2 eq.) in THF (4 mL) wasadded DIAD (176.74 mg, 874.06 umol, 169.95 uL, 2 eq.) at 0° C., thesolution was strried for 10 min at 0° C., then added ethanethioic S-acid(66.53 mg, 874.06 umol, 62.18 uL, 2 eq.), and then added compound 17b(140 mg, 437.03 umol, 1 eq.) after the solution was stirred for 10 minat 0° C., then the mixture was stirred at 25° C. for 1 hr. LC-MS showedcompound 17b was consumed completely and one main peak with desired MSwas detected. The mixture was concentrated in vacuo. The residue waspurified by prep-TLC (SiO₂, Petroleum ether:Ethyl acetate=1:1). Compound17c (165 mg, crude) was obtained as a yellow solid. TLC (Petroleumether:Ethyl acetate=1:1) R_(f)=0.05.

Step 4. Preparation of S-(((3aS,4S,6R,6aR)-6-(4-(N,N-di(tert-butoxycarbonyl))amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)ethanethioate (17d)

To a solution of compound 17c (165 mg, 435.99 umol, 1 eq.) in DCM (5 mL)was added TEA (352.95 mg, 3.49 mmol, 485.48 uL, 8 eq.) and Boc₂O (380.62mg, 1.74 mmol, 400.66 uL, 4 eq.). The mixture was stirred at 25° C. for12 hr. LC-MS showed one main peak with desired MS was detected. Thereaction was quenched by H₂O (5 mL), and then extracted with TBME (5mL*3), the organic phase was concentrated in vacuo. The crude productcompound 17d (252 mg, crude) was used into the next step without furtherpurification as a yellow oil. LCMS: (M+H⁺): 579.2.

Step 5. Preparation of tert-butyl(7-((3aR,4R,6S,6aS)-2,2,6a-trimethyl-6-((methylthio)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)carbamate(17e)

To a solution of compound 17d (252 mg, 435.48 umol, 1 eq.) in MeOH (2mL) and THF (2 mL) was added K₂CO₃ (120.37 mg, 870.95 umol, 2 eq.) andMeI (309.06 mg, 2.18 mmol, 135.55 uL, 5 eq.). The mixture was stirred at25° C. for 2 hr. LC-MS showed compound 17d was consumed completely andone main peak with desired MS was detected. The reaction was filteredand the filtrate was concentrated in cacuo. The residue was purified byprep-TLC (SiO₂, Petroleum ether:Ethyl acetate=3:1). The crude productcompound 17e (100 mg, crude) was used into the next step without furtherpurification as a yellow oil. TLC (Petroleum ether:Ethyl acetate=3:1)R_(f)=0.24.

Step 6. Preparation of(2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-2-((methylthio)methyl)tetrahydrofuran-3,4-diol(17)

A solution of compound 17e (100 mg, 221.95 umol, 1 eq.) in TFA (3.08 g,24.31 mmol, 2 mL, 90% purity, 109.53 eq.), The mixture was stirred at25° C. for 3 hr. LC-MS showed compound 17e was consumed completely andone main peak with desired MS was detected. The reaction wasconcentrated in vacuo at 25° C. The residue was purified by prep-HPLC.Compound 17 (46.96 mg, 135.40 umol, 61.00% yield, 100% purity, HCl salt)was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=9.41 (br s,1H), 8.80-8.48 (m, 1H), 8.41 (s, 1H), 7.74 (d, J=3.7 Hz, 1H), 7.06 (d,J=3.5 Hz, 1H), 6.08 (d, J=7.9 Hz, 1H), 5.49 (br s, 1H), 4.28 (d, J=7.7Hz, 1H), 3.99 (dd, J=4.3, 8.9 Hz, 1H), 2.85-2.71 (m, 2H), 2.03 (s, 3H),1.23 (s, 3H); ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ=8.38 (s, 1H), 7.73 (d,J=3.7 Hz, 1H), 7.02 (d, J=3.7 Hz, 1H), 6.08 (d, J=7.7 Hz, 1H), 4.27 (d,J=7.9 Hz, 1H), 3.99 (dd, J=4.3, 8.9 Hz, 1H), 2.83-2.69 (m, 2H), 2.02 (s,3H), 1.22 (s, 3H); LCMS: (M+H⁺): 311.1.

Example 19.(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(methoxymethyl)-3-methyltetrahydrofuran-3,4-diol(19)

Step 1. Preparation of((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(19a)

A mixture of compound 17a (600 mg, 1.35 mmol, 1 eq.) and NH₃ in MeOH (7M, 10 mL, 51.79 eq.) was stirred at 25° C. for 12 h. LCMS showed thedesired MS was observed. The mixture was concentrated. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=1/0 to 3:1). Compound 19a (450 mg, 1.32 mmol, 97.98% yield) wasobtained as white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.60 (s, 1H),7.29 (d, J=3.7 Hz, 1H), 6.60 (d, J=3.7 Hz, 1H), 6.17 (d, J=3.2 Hz, 1H),4.74 (d, J=3.1 Hz, 1H), 4.20 (dd, J=3.5, 5.6 Hz, 1H), 3.89-3.71 (m, 2H),1.61 (s, 3H), 1.57 (s, 3H), 1.38 (s, 3H); LCMS: (M+H⁺): 340.1.

Step 2. Preparation of4-chloro-7-((3aR,4R,6R,6aR)-6-(methoxymethyl)-2,2,6a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine(19b)

To a mixture of compound 19a (150 mg, 441.47 umol, 1 eq.) and MeI (4.56g, 32.13 mmol, 2 mL, 72.77 eq.) in THF (1 mL) was added NaH (26.49 mg,662.21 umol, 60% purity, 1.5 eq.) at 0° C. The mixture was stirred at25° C. for 1 h. TLC showed compound 19a was consumed and a new majorspot formed. The mixture was quenched by saturated NH₄Cl solution (10mL), extracted with EtOAc (5 mL×3). The combined organic layers weredried over Na₂SO₄, filtered and concentrated. The residue was purifiedby Prep-TLC (SiO₂, Petroleum ether/Ethyl acetate=2:1). Compound 19b (140mg, 395.70 umol, 89.63% yield) was obtained as a white solid. ¹H NMR(400 MHz, CHLOROFORM-d) δ=8.67 (s, 1H), 7.42 (d, J=3.7 Hz, 1H), 6.65 (d,J=3.7 Hz, 1H), 6.35-6.31 (m, 1H), 4.75 (d, J=2.4 Hz, 1H), 4.26 (dd,J=4.0, 7.1 Hz, 1H), 3.67-3.53 (m, 2H), 3.42-3.37 (m, 3H), 1.63 (s, 3H),1.61 (s, 3H), 1.42 (s, 3H); LCMS: (M+H⁺): 354.0; TLC (Petroleumether/Ethyl acetate=2:1) R_(f)=0.50.

Step 3. Preparation of7-((3aR,4R,6R,6aR)-6-(methoxymethyl)-2,2,6a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(19c)

A mixture of compound 19b (119.10 mg, 336.64 umol, 1 eq.) and NH₃.H₂O(47.19 mg, 336.64 umol, 51.86 uL, 25% purity, 1 eq.) in dioxane (5 mL)was stirred at 120° C. for 12 h. LCMS showed compound 19b was consumedand the desired MS was observed. The mixture was concentrated. Nofurther purification. Compound 19c (120 mg, crude) was obtained as awhite solid, which was used for next step with purification. ¹H NMR (400MHz, CHLOROFORM-d) δ=8.26 (s, 1H), 7.08 (d, J=3.7 Hz, 1H), 6.36 (d,J=3.5 Hz, 1H), 6.23 (d, J=2.2 Hz, 1H), 5.30 (br s, 2H), 4.65 (d, J=2.4Hz, 1H), 4.16 (dd, J=4.3, 7.2 Hz, 1H), 3.59-3.46 (m, 2H), 3.33 (s, 3H),1.55 (s, 3H), 1.53 (s, 3H), 1.34 (s, 3H); LCMS: (M+H⁺): 335.1.

Step 4. Preparation of(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(methoxymethyl)-3-methyltetrahydrofuran-3,4-diol(19)

A mixture of compound 19c (120 mg, 358.88 umol, 1 eq.) and HCl/MeOH (7M, 1 mL, 19.50 eq.) was stirred at 25° C. for 10 min. LCMS showedcompound 19c was consumed and the desired MS was observed. The mixturewas concentrated. The residue was purified by prep-HPLC (HCl condition).Compound 19 (50.11 mg, 150.54 umol, 41.95% yield, 99.37% purity. HClsalt) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=13.66(br s, 1H), 9.12 (br s, 1H), 8.39 (s, 1H), 7.66 (d, J=3.8 Hz, 1H), 7.01(d, J=3.7 Hz, 1H), 6.12 (d, =7.8 Hz, 1H), 5.40 (br s, 1H), 5.01 (br s,1H), 4.19 (d, J=7.8 Hz, 1H), 3.95 (t, J=3.5 Hz, 1H), 3.57-3.42 (m, 2H),3.34 (s, 3H), 1.24 (s, 3H); (¹H NMR 400 MHz, DMSO-d₆+D₂O) δ=8.36 (s,1H), 7.65 (d, J=3.7 Hz, 1H), 6.98 (d, J=3.7 Hz, 1H), 6.12 (d, J=7.8 Hz,1H), 4.18 (d, J=7.8 Hz, 1H), 3.94 (t, J=3.4 Hz, 1H), 3.57-3.39 (m, 2H),3.33 (s, 3H), 1.23 (s, 3H); LCMS: (M+H⁺): 295.2.

Example 20.(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-2-(phenoxymethyl)tetrahydrofuran-3,4-diol(20)

Step 1. Preparation of4-chloro-7-((3aR,4R,6R,6aR)-2,2,6a-trimethyl-6-(phenoxymethyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine(20a)

A mixture of compound 19a (200 mg, 588.63 umol, 1 eq.) and phenol (60.94mg, 647.49 umol, 56.95 uL, 1.1 eq.) in toluene (1 mL) was added CMBP(213.10 mg, 882.94 umol, 1.5 eq) at 25° C. under N₂. The mixture wasstirred at 80° C. for 12 h under N₂. LCMS showed compound 19a wasconsumed and the desired MS was observed. The mixture was concentrated.The residue was dissolved into water (5 mL). The mixture was extractedwith EtOAc (3 mL×3). The combined organic layers were dried over Na₂SO₄,filtered and concentrated. The residue was purified by prep-TLC (SiO₂,petroleum ether/ethyl acetate=3/1). Compound 20a (130 mg, crude) wasobtained as brown oil. LCMS: (M+H⁺): 416.2; ¹H NMR (400 MHz,CHLOROFORM-d) δ=8.70 (s, 1H), 7.46 (d, J=3.7 Hz, 1H), 7.32-7.29 (m, 1H),6.99 (t, J=7.2 Hz, 1H), 6.94-6.88 (m, 2H), 6.84 (d, J=7.5 Hz, 1H), 6.65(d, J=3.7 Hz, 1H), 6.39 (d, J=2.2 Hz, 1H), 4.86 (d, J=2.0 Hz, 1H), 4.52(dd, J=3.7, 6.8 Hz, 1H), 4.30-4.23 (m, 1H), 4.15-4.11 (m, 1H), 1.69 (s,3H), 1.66 (s, 3H), 1.47 (s, 3H).

Step 2. Preparation of7-((3aR,4R,6R,6aR)-2,2,6a-trimethyl-6-(phenoxymethyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(20b)

A mixture of compound 20a (130 mg, 312.60 umol, 1 eq.) and NH₃.H₂O (2.73g, 19.47 mmol, 3 mL, 62.30 eq.) in dioxane (3 mL) was stirred at 120° C.for 12 h. LCMS showed compound 20a was consumed and the desired MS wasobserved. The mixture was concentrated. The crude product was used fornext step without further purification. Compound 20b (123 mg, crude) wasobtained as brown oil. LCMS: (M+H⁺): 397.2.

Step 3. Preparation of(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-2-(phenoxymethyl)tetrahydrofuran-3,4-diol(20)

A mixture of compound 20b (123 mg, 310.26 umol, 1 eq.) in HCl/MeOH (4 M,4 mL, 51.57 eq.) was stirred at 25° C. for 0.5 h. LCMS showed compound20b was consumed and the desired MS was observed. The mixture wasconcentrated. The residue was purified by prep-HPLC (column: UniSil120*30*10 um; mobile phase: [water (0.05% HCl)-ACN]; B %: 5%-35%, 11min). Compound 20 (4.49 mg, 11.26 umol, 3.63% yield, 98.518% LCMSpurity, HCl salt) was obtained as a white solid. ¹H NMR (400 MHz,DMSO-d) δ=8.39 (s, 1H), 7.68 (d, J=3.7 Hz, 1H), 7.37-7.25 (m, 2H),7.07-6.91 (m, 4H), 6.18 (d, J=7.9 Hz, 1H), 4.38 (d, J=7.9 Hz, 1H),4.24-4.04 (m, 3H), 1.28 (s, 3H); ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ=8.38(s, 1H), 7.67 (d, J=3.7 Hz, 1H), 7.40-7.24 (m, 2H), 7.08-6.90 (m, 4H),6.19 (d, J=7.9 Hz, 1H), 4.38 (d, J=8.2 Hz, 1H), 4.23-4.03 (m, 3H), 1.28(s, 3H); LCMS: (M+H⁺): 357.1; LCMS purity 98.52%; HPLC purity: 100.00%.

Example 21.1-(3-(((2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxy-3-methyltetrahydrofuran-2-yl)methoxy)phenyl)ureahydrochloride (21)

Step 1. Preparation of4-chloro-7-((3aR,4R,6R,6aR)-2,2,6a-trimethyl-6-((3-nitrophenoxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine(21a)

A mixture of compound 19a (300 mg, 882.94 umol, 1 eq.) and 3-nitrophenol(122.82 mg, 882.94 umol, 175.46 uL, 1 eq.) in toluene (3 mL) was addedCMBP (426.20 mg, 1.77 mmol, 2 eq.) at 25° C. under N₂. The mixture wasstirred at 80° C. for 12 h under N₂. TLC showed the compound 19a wasconsumed and a major new spot was observed. The reaction solution wasconcentrated. The residue was dissolved in water (15 mL) and the mixturewas extracted with EtOAc (10 mL×3). The combined organic layers weredried over Na₂SO₄, filtered and concentrated. The residue was purifiedby prep-TLC (SiO₂, petroleum ether/ethyl acetate=3/1). Compound 21a (410mg, crude) was obtained as brown oil. TLC (Petroleum ether:Ethylacetate=3:1) R_(f)=0.6.

Step 2. Preparation of3-(((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)aniline(21b)

A mixture of compound 21a (410 mg, 889.63 umol, 1 eq.), Fe (248.41 mg,4.45 mmol, 5 eq.) and NH₄Cl (475.88 mg, 8.90 mmol, 311.03 uL, 10 eq.) inEtOH (5 mL) and H₂O (1 mL) was stirred at 75° C. for 1 h. LCMS showedthe compound 21a was consumed and the desired MS was observed. Themixture was filtered and concentrated. The residue was dissolved intowater (10 mL). The mixture was extracted with EtOAc (5 mL×4). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by prep-TLC (SiO₂, petroleumether/ethyl acetate=1/3). Compound 21b (100 mg, 168.91 umol, 26.09%,yield) was obtained as brown oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.69(s, 1H), 7.46 (d, J=3.8 Hz, 1H), 7.06 (t, J=8.1 Hz, 1H), 6.65 (d, J=3.7Hz, 1H), 6.39 (d, J=2.2 Hz, 1H), 6.32 (ddd, J=2.4, 5.0, 7.5 Hz, 2H),6.24-6.20 (m, 1H), 4.86 (d, J=2.3 Hz, 1H), 4.50 (dd, J=3.9, 6.5 Hz, 1H),4.22 (dd, J=3.8, 10.5 Hz, 1H), 4.10-4.05 (m, 1H), 1.66 (d, J=3.3 Hz,6H), 1.46 (s, 3H); LCMS: (M+H⁺): 431.1; TLC (Petroleum ether:Ethylacetate=1:3) R_(f)=0.8.

Step 3. Preparation of1-(3-(((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)phenyl)urea(21c)

To a mixture of compound 21b (100 mg, 232.08 umol, 1 eq.) in AcOH (1.6mL) and H2O (0.2 mL) was added the mixture of potassium cyanate (28.24mg, 348.12 umol, 13.71 uL, 1.5 eq.) in H₂O (0.3 mL) at 0° C. The mixturewas stirred at 25° C. for 12 h. LCMS showed the compound 1c was consumedand the desired MS was observed. The mixture was quenched by saturatedNaHCO₃solution to pH=8-9. The mixture was extracted with EtOAc (10mL×4). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by prep-TLC (SiO₂, petroleumether/ethyl acetate=1/3). Compound 21c (80 mg, 168.81 umol, 72.74%yield) was obtained as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d)δ=8.70 (s, 1H), 7.44 (d, J=3.7 Hz, 1H), 7.25-7.20 (m, 1H), 7.00 (s, 1H),6.85 (d, J=8.2 Hz, 1H), 6.69-6.65 (m, 2H), 6.38 (d, J=2.2 Hz, 1H), 6.27(s, 1H), 4.87 (d, J=2.2 Hz, 1H), 4.60 (br s, 2H), 4.53-4.46 (m, 2H),4.30-4.23 (m, 1H), 1.69 (s, 3H), 1.66 (s, 3H), 1.46 (s, 3H); LCMS:(M+H⁺): 474.2; TLC (Petroleum ether:Ethyl acetate=1:3) R_(f)=0.5.

Step 4. Preparation of1-(3-(((3aR,4R,6R,6aR)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)phenyl)urea(21d)

A mixture of compound 21c (75 mg, 158.26 umol, 1 eq.) in NH₃.H₂O (910.00mg, 6.49 mmol, 1 mL, 25% purity, 41.02 eq.) and dioxane (1 mL) wasstirred at 60° C. for 12 h. LCMS showed the compound 21c was remainedand the mixture was stirred at 80° C. for 2 h. TLC showed the compound21c was consumed. The crude product was used for next step withoutpurification. Compound 21d (70 mg, crude) was obtained as a brown solidwhich was used for next step without purification. LCMS: (M+H⁺): 455.2;TLC (Petroleum ether:Ethyl acetate=1:3) R_(f)=0.4.

Step 5. Preparation of1-(3-(((2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxy-3-methyltetrahydrofuran-2-yl)methoxy)phenyl)urea(21)

A mixture of compound 21d (70 mg, 154.02 umol, 1 eq.) in HCl/MeOH (4 M,2 mL, 51.94 eq.) was stirred at 25° C. for 1 h. LCMS showed the compound21d was consumed and the desired MS was observed. The mixture wasconcentrated. The residue was purified by prep-HPLC (column: UniSil120*30*10 um; mobile phase: [water (0.05% HCl)-ACN]; B %: 1%-30%, 11min). Compound 21 (33.54 mg, 74.39 umol, 48.30% yield, LCMS 100% purity,HCl) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆)=8.61 (brs, 1H), 8.41 (s, 1H), 7.72-7.65 (m, 1H), 7.28 (s, 1H), 7.17-7.11 (m,1H), 7.01 (br s, 1H), 6.86 (br d, J=7.9 Hz, 1H), 6.55 (br d, J=7.3 Hz,1H), 6.18 (d, J=7.7 Hz, 1H), 5.84 (br s, 2H), 4.37 (d, J=7.7 Hz, 1H),4.18 (s, 1H), 4.15-4.02 (m, 2H), 1.28 (s, 3H); ¹H NMR (400 MHz,DMSO-d₆+D₂O) δ=8.39 (s, 1H), 7.67 (d, J=3.7 Hz, 1H), 7.26 (s, 1H), 7.15(t, J=8.2 Hz, 1H), 6.98 (d, J=3.7 Hz, 1H), 6.84 (d, J=7.9 Hz, 1H), 6.57(br d, J=8.2 Hz, 1H), 6.18 (d, J=7.9 Hz, 1H), 4.36 (d, J=7.9 Hz, 1H),4.20-4.16 (m, 1H), 4.12-4.01 (m, 2H), 1.27 (s, 3H); LCMS: (M+H⁺): 415.1;LCMS purity 100.00%; HPLC purity: 100.00%.

Example 22.(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((3-(aminomethyl)phenoxy)methyl)-3-methyltetrahydrofuran-3,4-diol(22)

Step 1. Preparation of tert-butyl3-(((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)benzylcarbamate (22a)

To a mixture of compound 19a (80 mg, 235.45 umol, 1 eq.) and compoundInt-3 (57.83 mg, 259.00 umol, 1.1 eq.) in toluene (2 mL) was added CMBP(85.24 mg, 353.18 umol, 1.5 eq.) at 25° C. under N₂. LCMS showed thecompound 19a was consumed and the desired MS was observed. The mixturewas stirred at 80° C. for 12 h under N₂. The mixture was concentrated,and the residue was dissolved into water (10 mL). The mixture wasextracted with EtOAc (5 mL×3). The combined organic layers were driedover Na₂SO₄, filtered and concentrated. The residue was purified byprep-TLC (SiO₂, petroleum ether/ethyl acetate=3/1) to give compound 22a(90 mg, 165.13 umol, 70.13% yield) as brown oil. ¹H NMR (400 MHz,CHLOROFORM-d) δ=8.70 (s, 1H), 7.45 (d, J=3.7 Hz, 1H), 7.26-7.20 (m, 1H),6.93-6.73 (m, 4H), 6.66 (d, J=3.7 Hz, 1H), 6.39 (d, J=2.2 Hz, 1H), 4.85(d, J=2.2 Hz, 1H), 4.50 (dd, J=3.6, 6.7 Hz, 1H), 4.34-4.19 (m, 4H), 1.69(s, 3H), 1.66 (s, 3H), 1.48-1.46 (m, 12H); LCMS: (M+H⁺): 545.1;

Step 2. Preparation of tert-butyl3-(((3aR,4R,6R,6aR)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)benzylcarbamate (22b)

A mixture of compound 22a (90 mg, 165.13 umol, 1 eq.) and NH₃.H₂O (2.73g, 19.47 mmol, 3 mL, 117.94 eq.) in dioxane (3 mL) was stirred at 120°C. for 12 h. LCMS showed compound 22a was consumed and the desired MSwas observed. The mixture was concentrated to give compound 22b (86 mg,crude) as yellow oil which was used for next step without furtherpurification. LCMS: (M+H⁺): 526.2

Step 3. Preparation of(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((3-(aminomethyl)phenoxy)methyl)-3-methyltetrahydrofuran-3,4-diol(22)

A mixture of compound 22b (80 mg, 152.21 umol, 1 eq.) in HCl/MeOH (4 M,4 mL, 105.12 eq.) was stirred at 25° C. for 0.5 h. LCMS showed compound22b was consumed and the desired MS was observed. The mixture wasconcentrated. The residue was purified by prep-HPLC (part by column:UniSil 120*30*10 um; mobile phase: [water (0.05% HCl)-ACN]; B %: 1%-15%,11 min, to give the HCl salt, and the other part by column: AgelaDurashell C18 150*25 5 u; mobile phase: [water (0.04% NH₃H₂O)-ACN]; B %:5%-35%, 10 min) to give the free base.

Compound 22 (HCl salt) (7.85 mg, 18.61 umol, 12.22% yield, HCl salt,LCMS purity 100.0%) was obtained as a gray solid. ¹H NMR (400 MHz,DMSO-d₆) δ=8.39 (s, 1H), 8.33 (br s, 3H), 7.69 (d, J=3.7 Hz, 1H), 7.37(t, J=7.9 Hz, 1H), 7.22 (s, 1H), 7.10-7.00 (m, 3H), 6.19 (d, J=7.9 Hz,1H), 5.53 (br s, 1H), 5.21 (s, 1H), 4.39 (d, J=8.1 Hz, 1H), 4.24-4.09(m, 3H), 4.02 (br d, J=5.7 Hz, 2H), 1.30 (s, 3H); ¹H NMR (400 MHz,DMSO-d₆+D₂O) δ=8.38 (s, 1H), 7.66 (d, J=3.8 Hz, 1H), 7.38 (t, J=7.9 Hz,1H), 7.17 (s, 1H), 7.10-7.03 (m, 2H), 6.98 (d, J=3.4 Hz, 1H), 6.19 (d,J=7.9 Hz, 1H), 4.38 (d, J=8.1 Hz, 1H), 4.24-4.08 (m, 3H), 4.05-3.98 (m,2H), 1.29 (s, 3H); LCMS: (M+H⁺): 386.2.

Compound 22 (free base) (21.67 mg, 55.74 umol, 36.62% yield, LCMS purity99.13%) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=8.06(s, 1H), 7.37 (d, J=3.7 Hz, 1H), 7.22 (t, J=7.9 Hz, 1H), 6.99 (br s,3H), 6.91 (d, J=7.5 Hz, 1H), 6.82 (dd, J=2.3, 8.1 Hz, 1H), 6.60 (d,J=3.7 Hz, 1H), 6.15 (d, J=7.9 Hz, 1H), 5.38 (br s, 1H), 5.01 (br s, 1H),4.38 (br d, J=7.6 Hz, 1H), 4.17-4.02 (m, 3H), 3.69 (s, 2H), 1.28 (s,3H); ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ=8.05 (s, 1H), 7.35 (d, J=3.8 Hz,1H), 7.21 (t, J=7.8 Hz, 1H), 6.98 (s, 1H), 6.90 (d, J=7.7 Hz, 1H), 6.81(dd, J=2.1, 7.9 Hz, 1H), 6.59 (d, J=3.7 Hz, 1H), 6.14 (d, J=8.1 Hz, 1H),4.37 (d, J=8.1 Hz, 1H), 4.16-4.01 (m, 3H), 3.65 (s, 2H), 1.26 (s, 3H);LCMS: (M+H⁺): 386.3

Example 26.(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(4-chlorophenyl)(hydroxy)methyl)-3-methyltetrahydrofuran-3,4-diol(26)

Step 1. Preparation of(3aS,4S,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylicacid (26a)

To a mixture of compound 19a (500 mg, 1.47 mmol, 1 eq.),diacetoxyiodobenzene (DAIB) (1.04 g, 3.24 mmol, 2.2 eq.) in MeCN (2 mL)and H₂O (2 mL) was added TEMPO (46.28 mg, 294.31 umol, 0.2 eq.) at 0° C.The mixture was stirred at 25° C. for 1 h. TLC showed the compound 19awas consumed. The mixture was concentrated. The residue was dissolved intoluene (10 mL). The mixture was concentrated. The crude product wasused for next step without further purification. Compound 26a (520 mg,crude) was obtained as brown oil. TLC (SiO₂, ethyl acetate/ethanol=1/1):R_(f)=0.5.

Step 2. Preparation of(3aS,4S,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-methoxy-N,2,2,3a-tetramethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide(26b)

To a mixture of compound 26a (520 mg, 1.47 mmol, 1 eq.),N-methoxymethanamine (215.07 mg, 2.20 mmol, 1.5 eq., HCl), pyridine(348.82 mg, 4.41 mmol, 355.93 uL, 3 eq.) in EtOAc (5 mL) was added T3P(1.87 g, 2.94 mmol, 1.75 mL, 50% purity, 2 eq.) at 25° C. The mixturewas stirred at 25° C. for 12 h. TLC showed the compound 26a wasconsumed. The mixture was quenched by water (50 mL) and extracted withEtOAc (25 mL×3). The combined organic layers were dried over Na₂SO₄,filtered and concentrated. The residue was purified by prep-TLC (SiO₂,Petroleum ether/Ethyl acetate=1/1). Compound 26b (450 mg, 1.13 mmol,77.15% yield) was obtained as colorless oil. ¹H NMR (400 MHz,CHLOROFORM-d) δ=8.67 (s, 1H), 8.21 (d, J=3.7 Hz, 1H), 6.69-6.63 (m, 2H),5.26 (s, 1H), 4.60 (d, J=1.3 Hz, 1H), 3.79 (s, 3H), 3.28 (s, 3H), 1.70(s, 3H), 1.46 (d, J=3.5 Hz, 6H); LCMS: (M+H⁺): 397.2; TLC (SiO₂,petroleum ether/ethyl acetate=1/1): R_(f)=0.6.

Step 3. Preparation of((3aS,4S,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)(4-chlorophenyl)methanone(26c)

To a mixture of compound 26b (200 mg, 504.00 umol, 1 eq.) in THF (2 mL)was added bromo-(4-chlorophenyl)magnesium (1 M, 1.01 mL, 2 eq.) at −10°C. under N₂. The mixture was stirred at 0° C. for 1 h under N₂. TLCshowed the compound 26b was consumed. The mixture was quenched bysaturated NH₄Cl solution (10 mL), extracted with EtOAc (5 mL×3). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by prep-TLC (SiO₂, Petroleumether/Ethyl acetate=3/1). Compound 26c (200 mg, 446.13 umol, 88.52%yield) was obtained as colorless oil. LCMS: (M+H⁺): 448.1; TLC (SiO₂,Petroleum ether/Ethyl acetate=3/1): R_(f)=0.6.

Step 4. Preparation of(R)-((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)(4-chlorophenyl)methanol(26d)

To a mixture of compound 26c (200 mg, 446.13 umol, 1 eq.) in toluene (2mL) was added DIBAL-H (1 M, 892.26 uL, 2 eq.) at -70° C. under N₂. Themixture was stirred at −70° C. for 0.5 h under N₂. TLC showed thecompound 26c was consumed. The mixture was quenched by water (0.5 mL),15% NaOH solution (0.5 mL), water (0.5 mL) and the mixture was stirredfor 10 min. The mixture was dried over MgSO₄, filtered and concentrated.The residue was purified by prep-TLC (SiO₂, Petroleum ether/Ethylacetate=3/1). Compound 26d (190 mg, 421.93 umol, 94.57% yield) wasobtained as colorless oil. ¹H NMR (400 MHz, CHLOROFORM-d)=8.68 (s, 1H),7.39-7.30 (m, 5H), 6.68 (d, J=3.7 Hz, 1H), 6.19 (d, J=2.6 Hz, 1H), 4.84(d, J=8.4 Hz, 1H), 4.72 (d, J=2.6 Hz, 1H), 4.14 (d, J=8.4 Hz, 1H), 2.64(br d, J=0.7 Hz, 1H), 1.85 (s, 3H), 1.67 (s, 3H), 1.43 (s, 3H); TLC(SiO₂, petroleum ether/ethyl acetate=1/1): R_(f)=0.4.

Step 5. Preparation of(R)-((3aR,4R,6R,6aR)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)(4-chlorophenyl)methanol(26e)

A mixture of compound 26d (140 mg, 310.89 umol, 1 eq.) in NH₃.H₂O (1.59g, 11.36 mmol, 1.75 mL, 25% purity, 36.54 eq.) and dioxane (2 mL) wasstirred at 100° C. for 12 h. LCMS showed the compound 26d was consumedand the desired MS was observed. The mixture was concentrated. The crudeproduct was used for next step without further purification. Compound26e (133 mg, crude) was obtained as a lightyellow oil which was used fornext step without further purification. LCMS: (M+H⁺): 431.1.

Step 6. Preparation of(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(4-chlorophenyl)(hydroxy)methyl)-3-methyltetrahydrofuran-3,4-diol(26)

A mixture of compound 26e (133 mg, 308.67 umol, 1 eq.) in HCl/MeOH (4 M,1.77 mL, 22.98 eq.) was stirred at 25° C. for 1 h. LCMS showed thecompound 26e was consumed and the desired MS was observed. The mixturewas concentrated. The residue was purified by prep-HPLC (column: WatersXbridge 150*25 5 u; mobile phase: [water (0.04% NH₃H₂O+10 Mm,NH₄HCO₃)-ACN]; B %: 10%-40%, 10 min). Compound 26 (56.96 mg, 145.24umol, 47.05% yield, LCMS 99.65% purity) was obtained as a white solid.¹H NMR (400 MHz, DMSO-d) 5=8.04 (s, 1H), 7.45-7.37 (m, 3H), 7.31 (d,J=8.4 Hz, 2H), 7.08 (br s, 2H), 6.63-6.55 (m, 2H), 5.84 (d, J=8.1 Hz,1H), 5.24 (d, J=7.1 Hz, 1H), 4.87-4.79 (m, 1H), 4.74 (s, 1H), 4.43 (brt, J=7.5 Hz, 1H), 4.06 (d, J=5.7 Hz, 1H), 1.15 (s, 3H); ¹H NMR (400 MHz,DMSO-d₆+D₂O) δ=8.02 (s, 1H), 7.43-7.26 (m, 5H), 6.58 (d, J=3.5 Hz, 1H),5.82 (d, J=8.1 Hz, 1H), 4.79 (d, J=5.7 Hz, 1H), 4.39 (d, J=8.2 Hz, 1H),4.06 (d, l=5.7 Hz, 1H), 1.13 (s, 3H); LCMS: (M+H⁺): 391.0; LCMS purity99.65%; HPLC purity: 100.00%.

Example 32.7-((2R,3R,4S,5R)-5-(((2-aminoquinolin-7-yl)oxy)methyl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)-1H-pyrrolo[2,3-d]pyrimidin-4(7H)-oneO-methyl oxime (32)

Step 1. Preparation of7-(((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-N-tritylquinolin-2-amine(32a)

To a solution of compound 19a (150 mg, 441.47 umol, 1 eq.) and compoundInt-5 (230 mg, 571.45 umol, 1.29 eq.) in toluene (3 mL) was added2-(tributyl-phosphanylidene)acetonitrile (213.10 mg, 882.94 umol, 2 eq.)under N₂ at 25° C. The mixture was stirred at 80° C. for 12 h. LC-MSshowed compound 19a was remained. Several new peaks were shown on LC-MSand desired compound 32a was detected. The reaction mixture wasconcentrated under reduced pressure to remove solvent. The residue waspurified by prep-TLC (SiO₂, Petroleum ether/Ethyl acetate=3:1) and basedon TLC (Petroleum ether/Ethyl acetate=3:1, R_(f)=0.37). Compound 32a(0.13 g, crude) was obtained as a yellow solid. TLC (Petroleumether:Ethyl acetate=3:1) R_(f)=0.37; LCMS: (M+1-): 724.2.

Step 2. Preparation of7-((3aR,4R,6R,6aR)-2,2,6a-trimethyl-6-(((2-(tritylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-1H-pyrrolo[2,3-d]pyrimidin-4(7H)-oneO-methyl oxime (32b)

To a solution of compound 32a (120 mg, 165.69 umol, 1 eq.) in t-BuOH (2mL) was added O-methylhydroxylamine hydrochloride (110.70 mg, 1.33 mmol,100.64 uL, 8 eq.) under N₂. The mixture was stirred at 80° C. for 16 h.LC-MS showed compound 32a was almost consumed. Several new peaks wereshown on LC-MS and desired compound 32b was detected. The reactionmixture was concentrated under reduced pressure to remove solvent. Theresidue was added aq. NaHCO₃and extracted with DCM (5 mL×2) and EtOAc (5mL×2), the organic layer was washed with brine (10 mL×2), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by prep-TLC (SiO₂, Petroleumether/Ethyl acetate=2:3, R_(f)=0.57) and based on TLC (Petroleumether:Ethyl acetate=2:3 R_(f)=0.57). Compound 32b (0.1 g, 134.67 umol,81.28% yield, 98.96% purity) was obtained as a yellow solid. LCMS1:(M+H⁺): 735.2; TLC (Petroleum ether:Ethyl acetate=2:3) R_(f)=0.57;LCMS2: (M+H⁺): 735.5. LCMS purity 98.96%. ¹H NMR (400 MHz, CHLOROFORM-d)δ=7.35-7.44 (m, 6.6H), 7.28-7.33 (m, 3.6H), 7.19-7.26 (m, 3H), 7.01 (brs, 0.7H), 6.83-6.91 (m, 1H), 6.66 (br d, J=3.67 Hz, 0.4H), 6.39-6.52 (m,1.5H), 6.25 (s, 0.4H), 6.04 (d, J=8.93 Hz, 0.7H), 4.81 (s, 0.4H), 4.66(s, 0.4H), 4.42-4.58 (m, 0.9H), 4.18-4.39 (m, 1.8H), 3.88 (d, J=5.62 Hz,2.4H), 1.52-1.73 (m, 4.7H), 1.44 (br d, J=5.75 Hz, 3H), 0.80-0.93 (m,1H).

Step 3. Preparation of7-((2R,3R,4S,5R)-5-(((2-aminoquinolin-7-yl)oxy)methyl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)-1H-pyrrolo[2,3-d]pyrimidin-4(7H)-oneO-methyl oxime (32)

To a solution of compound 32b (0.1 g, 136.08 umol, 1 eq.) was added TFA(1.54 g, 12.16 mmol, 1 mL, 90% purity, 89.32 eq.). The mixture wasstirred at 25° C. for 2 h. LC-MS showed compound 32b was consumedcompletely and one main peak with desired product compound 32 wasdetected. The reaction mixture was added NH₃.H₂O adjusted pH around 8and concentrated under reduced pressure to remove solvent. The residuewas purified by prep-HPLC (basic condition column: Waters Xbridge 150*255 u; mobile phase: [water (0.04% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %:5%-35%, 10 min). Compound 32 (8.59 mg, 18.25 umol, 13.41% yield, 96.15%LCMS purity) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ7.79 (d, J=8.77 Hz, 0.6H), 7.54 (d, J=9.21 Hz, 0.7H), 7.48 (s, 0.4H),7.21 (d, J=3.51 Hz, 0.4H), 6.92 (br d, J=7.45 Hz, 0.6H), 6.81-6.89 (m,0.6H), 6.56-6.62 (m, 0.9H), 6.33 (s, 1.5H), 6.25 (d, J=3.07 Hz, 0.6H),6.00 (d, J=8.33 Hz, 0.4H), 5.41 (br d, J=6.58 Hz, 0.6H), 4.99-5.06 (m,0.5H), 4.33 (t, J=7.89 Hz, 0.4H), 4.10-4.24 (m, 2.2H), 3.71 (s, 2.2H),3.32 (br s, 1.1H), 1.23-1.34 (m, 3H); ¹H NMR (400 MHz, DMSO-d₆+D₂O)δ=7.82 (s, 0.3H), 7.80 (s, 0.3H), 7.56 (d, J=9.21 Hz, 0.7H), 7.51 (s,0.4H), 7.19 (d, J=3.07 Hz, 0.4H), 6.90-6.94 (m, 0.7H), 6.84-6.90 (m,0.7H), 6.62 (s, 0.3H), 6.57-6.60 (m, 0.6H), 6.27 (d, J=3.07 Hz, 0.5H),5.99 (d, J=7.89 Hz, 0.4H), 4.33 (d, J=7.89 Hz, 0.5H), 4.18 (br s, 0.8H),4.14 (br s, 1.1H), 4.09-4.13 (m, 0.5H), 1.24-1.30 (m, 3H); LCMS1:(M+H⁺): 453.2; LCMS: (M+H⁺): 453.3; LCMS purity 96.15%; HPLC purity:100.00%.

Example 37.7-((2R,3R,4S,5R)-5-((R)-(3,4-dichlorophenyl)(hydroxy)methyl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)-1H-pyrrolo[2,3-d]pyrimidin-4(7H)-oneO-methyl oxime (37)

Step 1. Preparation of((3aS,4S,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)(3,4-dichlorophenyl)methanone(37a)

To a solution of compound 26b (1 g, 2.52 mmol, 1 eq.) in THF (15 mL) wasadded compound Int-6 (1 M, 10.08 mL, 4 eq.) at −10° C. under N₂. Themixture was stirred at 0° C. for 5 min. TLC indicated compound 26b wasconsumed completely and many new spots formed. The reaction was cleanaccording to TLC (Petroleum ether:Ethyl acetate=3:1 R_(f)=0.48). Thesolution was added aq. sat. NH₄Cl (15 mL) and extracted with DCM (10mL×2). The combined organic layers were washed with brine (20 mL×2),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=1/0 to 15/1) and based on TLC (Petroleumether:Ethyl acetate=3:1 R_(f)=0.48). Compound 37a (660 mg, 1.27 mmol,50.42% yield, LCMS purity 92.94%) was obtained as a white solid. ¹H NMR(400 MHz, CHLOROFORM-d) δ=8.64-8.73 (m, 1H), 8.28 (d, J=2.19 Hz, 1H),7.99 (dd, J=8.33, 2.19 Hz, 1H), 7.89 (d, J=3.95 Hz, 1H), 7.63 (d, J=8.33Hz, 1H), 6.72 (d, J=3.95 Hz, 1H), 6.59 (d, J=1.32 Hz, 1H), 5.54 (s, 1H),4.70 (d, J=1.32 Hz, 1H), 1.83 (s, 3H), 1.47 (s, 3H), 1.36 (s, 3H); LCMS:(M+H⁺): 483.9, LCMS purity 92.94%; TLC (Petroleum ether:Ethylacetate=3:1) R_(f)=0.48.

Step 2. Preparation of(R)-((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)(3,4-dichlorophenyl)methanol(37b)

To a solution of compound 37a (660 mg, 1.37 mmol, 1 eq.) in toluene (10mL) was added DIBAL-H (1 M, 2.73 mL, 2 eq.) at -70° C. under N₂. Themixture was stirred at −70° C. for 5 min. TLC indicated compound 37a wasconsumed completely and one new spot formed. The reaction was cleanaccording to TLC (Petroleum ether:Ethyl acetate=3:1 R_(f)=0.30). Thereaction solution was added aq. sat. seignette salt (30 mL) and MTBE (20mL) stirred at 25° C. for 0.5 h and extracted with MTBE (10 mL×4),washed with brine (10 mL×2), dried Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified bycolumn chromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 1/1)and based on TLC (Petroleum ether:Ethyl acetate=3:1 R_(f)=0.30).Compound 37b (310 mg, 513.06 umol, 37.53% yield, LCMS purity 80.23%) wasobtained as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.67 (s,1H), 7.52 (d, J=1.75 Hz, 1H), 7.40 (d, J=8.33 Hz, 1H), 7.31 (d, J=3.51Hz, 1H), 7.22 (dd, J=8.33, 1.75 Hz, 1H), 6.69 (d, J=3.95 Hz, 1H), 6.17(d, J=2.63 Hz, 1H), 4.83 (d, J=8.33 Hz, 1H), 4.76 (d, J=2.63 Hz, 1H),4.05-4.18 (m, 1H), 2.94 (br s, 1H), 1.84 (s, 3H), 1.67 (s, 3H), 1.43 (s,3H); LCMS: (M+H⁺): 484.3. LCMS purity 80.23%; TLC (Petroleum ether:Ethylacetate=3:1) R_(f)=0.30.

Step 3. Preparation of 7-((3aR,4R,6R,6aR)-6-((R)-(3,4-dichlorophenyl)(hydroxy)methyl)-2,2,6a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-1H-pyrrolo[2,3-d]pyrimidin-4(7H)-one O-methyl oxime (37c)

To a solution of compound 37b (0.1 g, 206.29 umol, 1 eq.) in t-BuOH (1mL) was added O-methylhydroxylamine hydrochloride (137.83 mg, 1.65 mmol,125.30 uL, 8 eq.) under N₂ at 25° C. The mixture was stirred at 80° C.for 16 h. LC-MS showed no compound 37b was remained. Several new peakswere shown on LC-MS and desired compound was detected. The reactionmixture was concentrated under reduced pressure to remove solvent.Compound 37c (100 mg, crude) was used into the next step without furtherpurification as a pink solid. LCMS: (M+H⁺): 495.4.

Step 4. Preparation of7-((2R,3R,4S,5R)-5-((R)-(3,4-dichlorophenyl)(hydroxy)methyl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)-1H-pyrrolo[2,3-d]pyrimidin-4(7H)-oneO-methyl oxime (37)

To a solution of compound 37c (100.00 mg, 201.88 umol, 1 eq.) was addedHCl/MeOH (4 M, 5 mL, 99.07 eq.) at 0° C. The mixture was stirred at 25°C. for 10 min. LC-MS showed compound 1b was consumed completely and onemain peak with desired MS was detected. The reaction mixture wasconcentrated under reduced pressure to remove solvent at 25° C. Theresidue was added NH₃.H₂O to adjusted pH around 8. The residue waspurified by prep-HPLC (basic condition, column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH₃H2O+10 mM NH₄HCO₃)-ACN]; B %: 10%-40%,10 min). Compound 37 (18.03 mg, 39.00 umol, 19.32% yield, 98.48% LCMSpurity) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=10.93(br s, 0.6H), 10.64 (br s, 0.4H), 7.43-7.63 (m, 3H), 7.31-7.40 (m, 1H),7.28 (br s, 0.6H), 6.57 (br s, 0.3H), 6.24 (br s, 1H), 5.97 (br s, 1H),5.78 (br d, J=8.33 Hz, 0.6H), 5.30 (br s, 1H), 4.78-4.88 (m, 1.3H), 4.74(br s, 0.6H), 4.40 (br s, 0.4H), 4.27 (br s, 0.6H), 3.97 (br d, 1=6.58Hz, 0.3H), 3.89 (br d, J=7.02 Hz, 0.5H), 3.65-3.79 (m, 3H), 1.24 (br s,3H); ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ=7.51 (br d, J=19.73 Hz, 2.5H),7.28-7.39 (m, 1H), 7.23 (br s, 0.6H), 6.57 (br s, 0.3H), 6.26 (br s,0.5H), 5.92 (br s, 0.2H), 5.75 (br d, J=8.33 Hz, 0.5H), 4.67-4.81 (m,0.8H), 4.39 (br s, 0.3H), 4.25-4.26 (m, 0.5H), 3.96 (br s, 0.5H), 3.89(br d, J=7.45 Hz, 0.8H), 1.22 (br s, 3H); LCMS: (M+H⁺): 455.1. LCMSpurity 98.48%; HPLC purity: 98.50%.

Example 40.(2S,3S,4R,5R)-3-methyl-5-(4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((methylthio)methyl)tetrahydrofuran-3,4-diol(40)

Step 1. Preparation of tert-butylmethyl(7-((3aR,4R,6S,6aS)-2,2,6a-trimethyl-6-((methylthio)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)carbamate(40a)

To a solution of compound 17d in MeOH (1 mL) and THF (1 mL) was addedK₂CO₃ (95.53 mg, 691.23 umol, 2 eq.) and MeI (245.28 mg, 1.73 mmol,107.58 uL, 5 eq.). The mixture was stirred at 25° C. for 2 hr. LC-MSshowed compound 17d was consumed completely and one main peak withdesired MS was detected. The reaction was filtered, and the filtrate wasconcentrated in vacuo. The residue was purified by prep-TLC (SiO₂,Petroleum ether:Ethyl acetate=3:1). The crude product compound 40a (60mg, crude) was used into the next step without further purification as ayellow oil. TLC (Petroleum ether:Ethyl acetate=3:1) R_(f)=0.24.

Step 2. Preparation of(2S,3S,4R,5R)-3-methyl-5-(4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((methylthio)methyl)tetrahydrofuran-3,4-diol(40)

A solution of compound 40a (103.11 mg, 221.95 umol, 1 eq.) in TFA (3.08g, 24.31 mmol, 2.00 mL, 90% purity, 109.53 eq.), the mixture was stirredat 25° C. for 3 hr. LC-MS showed compound 40a was consumed completelyand one main peak with desired MS was detected. The reaction wasconcentrated in vacuo at 25° C. The residue was purified by prep-HPLC.Compound 40 (6.78 mg, 19.77 umol, 8.91% yield, 94.59% purity) wasobtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=8.15 (s, 1H),7.47 (br s, 1H), 7.35 (br s, 1H), 6.60 (br s, 1H), 6.02 (br d, J=7.7 Hz,1H), 5.32 (br d, J=6.6 Hz, 1H), 4.90 (s, 1H), 4.30 (br t, J=6.6 Hz, 1H),3.93 (br s, 1H), 2.95 (br s, 3H), 2.83-2.70 (m, 2H), 2.01 (s, 3H), 1.22(s, 3H); ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ=8.13 (s, 1H), 7.33 (d, J=3.7Hz, 1H), 6.59 (d, J=3.7 Hz, 1H), 6.01 (d, J=7.7 Hz, 1H), 4.28 (d, J=7.9Hz, 1H), 3.92 (dd, J=4.2, 8.8 Hz, 1H), 2.93 (s, 3H), 2.80-2.67 (m, 2H),2.00 (s, 3H), 1.21 (s, 3H), LCMS: (M+H⁺): 325.1.

Example 41.1-(3-(((2R,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxy-3-methyltetrahydrofuran-2-yl)methoxy)phenyl)urea(41)

A mixture of compound 21c (50 mg, 105.51 umol, 1 eq.) in TFA (1 mL) andH₂O (0.2 mL) was stirred at 25° C. for 0.5 h. LCMS showed the compound21c was consumed and the desired MS was observed. The mixture wasconcentrated. The residue was dissolved in aq. saturated NaHCO₃ (10 mL)and the mixture was extracted with EtOAc (5 mL×3). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated. The residuewas purified by prep-HPLC (column: Waters Xbridge 150*25 5 u; mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 5%-30%, 11 min).Compound 41 (11.81 mg, 27.22 umol, 25.80% yield, LCMS 100% purity, freebase) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=8.69(s, 1H), 8.55 (s, 1H), 7.95 (d, J=3.8 Hz, 1H), 7.25 (s, 1H), 7.14 (t,J=8.1 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 6.77 (d, J=3.8 Hz, 1H), 6.56 (dd,J=2.1, 8.2 Hz, 1H), 6.28 (d, J=7.8 Hz, 1H), 5.85 (s, 2H), 5.54 (br s,1H), 5.13 (br s, 1H), 4.45 (br d, J=7.9 Hz, 1H), 4.24-4.02 (m, 3H), 1.29(s, 3H); ¹H NMR (400 MHz, DMSO-d₆) δ=8.66 (s, 1H), 7.89 (d, J=3.9 Hz,1H), 7.22 (s, 1H), 7.15 (t, J=8.1 Hz, 1H), 6.85 (d, J=8.2 Hz, 1H), 6.76(d, J=3.8 Hz, 1H), 6.57 (dd, J=2.2, 8.2 Hz, 1H), 6.26 (d, J=7.9 Hz, 1H),4.43 (d, J=8.1 Hz, 1H), 4.21-4.16 (m, 1H), 4.14-4.02 (m, 2H), 1.27 (s,3H); LCMS: (M+H⁺): 434.2; LCMS purity 100.00%; HPLC purity: 100.00%.

Example 42.(2S,3S,4R,5R)—N-(3-(aminomethyl)phenyl)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxy-3-methyltetrahydrofuran-2-carboxamide(42)

Step 1. Preparation of tert-butyl3-((3aS,4S,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamido)benzylcarbamate(42a)

To a mixture of compound 26a (300 mg, 848.04 umol, 1 eq.), compoundInt-3 (282.76 mg, 1.27 mmol, 1.5 eq.) and pyridine (201.24 mg, 2.54mmol, 205.35 uL, 3 eq.) in EtOAc (3 mL) was added T3P (2.16 g, 3.39mmol, 2.02 mL, 50% purity, 4 eq.) at 0° C. under N₂. The mixture wasstirred at 25° C. for 12 h. TLC showed the compound 26a was consumed.The mixture was quenched by water (10 mL) and extracted with EtOAc (5mL×3). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by prep-TLC (SiO₂, petroleumether/ethyl acetate=1/1). Compound 42a (360 mg, 645.13 umol, 76.07%yield) was obtained as a brown solid. TLC (SiO₂, petroleum ether/ethylacetate=1/1): R_(f)=0.6; ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.70 (s, 1H),8.50-8.37 (m, 1H), 7.47 (s, 1H), 7.42-7.34 (m, 2H), 7.31-7.28 (m, 1H),7.07 (br d, J=7.6 Hz, 1H), 6.76 (d, J=3.7 Hz, 1H), 6.28 (d, J=2.9 Hz,1H), 4.88 (br d, J=2.8 Hz, 2H), 4.71 (s, 1H), 4.29 (br d, J=5.5 Hz, 2H),1.81 (s, 3H), 1.69 (s, 3H), 1.45 (s, 12H).

Step 2. Preparation of(2S,3S,4R,5R)—N-(3-(aminomethyl)phenyl)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxy-3-methyltetrahydrofuran-2-carboxamide(42)

A mixture of compound 42a (100 mg, 179.20 umol, 1 eq.) in TFA (2 mL) andH₂O (0.2 mL) was stirred at 25° C. for 12 h. LCMS showed the compound42a was consumed and the desired MS was observed. The mixture wasquenched by saturated NaHCO₃solution to pH=8-9. The mixture was filteredand concentrated. The residue was purified by prep-HPLC (column: WatersXbridge 150*25 5 u; mobile phase: [water (0.04% NH₃.H₂O)-ACN]; B %:1%-30%, 10 min). Compound 42 (22.04 mg, 58.56 umol, 32.68% yield, LCMS97.87% purity) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ=10.41 (s, 1H), 8.71-8.66 (m, 1H), 8.44 (d, J=3.7 Hz, 1H), 7.62 (s,1H), 7.58-7.45 (m, 1H), 7.28 (t, J=7.7 Hz, 1H), 7.09 (d, J=7.7 Hz, 1H),6.84 (d, J=3.5 Hz, 1H), 6.41 (d, J=7.9 Hz, 1H), 5.73-5.44 (m, 2H), 4.56(s, 1H), 4.40 (br d, J=7.5 Hz, 1H), 3.72 (s, 2H), 1.24 (s, 3H); ¹H NMR(400 MHz, DMSO-d) δ=8.66 (s, 1H), 8.37 (d, J=3.7 Hz, 1H), 7.56 (s, 1H),7.47 (br d, J=8.2 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.10 (d, J=8.2 Hz,1H), 7.03 (s, 1H), 6.82 (d, J=3.7 Hz, 1H), 6.38 (d, J=7.9 Hz, 1H), 4.52(s, 1H), 4.40 (d, J=7.9 Hz, 1H), 1.22 (s, 3H); LCMS: (M+H⁺): 418.0; LCMSpurity: 97.87%; HPLC purity: 99.08%.

Example 43.(2S,3S,4R,5R)—N-(3-(aminomethyl)phenyl)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxy-3-methyltetrahydrofuran-2-carboxamide(43)

To mixture of compound 42 (89 mg, 213.00 umol, 1 eq.) in saturatedNaHCO₃solution (5 mL) and dioxane (2 mL) was added NH₃.H₂O (1.82 g,12.98 mmol, 2 mL, 25% purity, 60.95 eq.) at 25° C. The mixture wasstirred at 67° C. for 12 h. LCMS showed the compound 42 was consumed andthe desired MS was observed. The mixture was concentrated. The residuewas dissolved in MeCN (10 mL), filtered and concentrated. The residuewas purified by prep-HPLC (column: UniSil 120*30*10 um; mobile phase:[water (0.05% HCl)-ACN]; B %: 1%-15%, 11 min). Compound 43 (12.61 mg,26.21 umol, 12.31% yield, LCMS 97.98% purity, 2HCl) was obtained as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ=10.66 (s, 1H), 8.49-8.32 (m,5H), 8.16 (d, J=3.7 Hz, 1H), 7.82 (s, 1H), 7.58 (br d, J=8.2 Hz, 1H),7.41 (t, J=7.8 Hz, 1H), 7.29-7.23 (m, 1H), 7.09 (d, J=3.7 Hz, 1H), 6.29(d, J=7.9 Hz, 1H), 5.92-5.28 (m, 2H), 4.60 (s, 1H), 4.36 (d, J=7.9 Hz,1H), 4.05-3.98 (m, 2H), 3.85 (s, 1H), 1.23 (s, 3H); ¹H NMR (400 MHz,DMSO-d₆+D₂O) δ=10.65 (s, 1H), 8.36 (s, 1H), 8.13 (d, J=3.8 Hz, 1H), 7.77(d, J=1.7 Hz, 1H), 7.57 (br d, J=8.1 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H),7.22 (d, J=7.8 Hz, 1H), 7.02 (d, J=3.7 Hz, 1H), 6.28 (d, J=7.9 Hz, 1H),4.56 (s, 1H), 4.35 (d, J=7.9 Hz, 1H), 4.01 (s, 2H), 1.23 (s, 3H); LCMS:(M+H⁺): 399.1; LCMS purity 97.98%; HPLC purity: 98.57%.

Example 44.7-((2R,3R,4S,5R)-5-((R)-(4-chlorophenyl)(hydroxy)methyl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)-1H-pyrrolo[2,3-d]pyrimidin-4(7H)-oneO-methyl oxime (44)

Step 1. Preparation of7-((3aR,4R,6R,6aR)-6-((R)-(4-chlorophenyl)(hydroxy)methyl)-2,2,6a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-1H-pyrrolo[2,3-d]pyrimidin-4(7H)-oneO-methyl oxime (44a)

A mixture of compound 26d (130 mg, 288.69 umol, 1 eq.) andO-methylhydroxylamine hydrochloride (192.88 mg, 2.31 mmol, 175.35 uL, 8eq.) in t-BuOH (3 mL) was stirred at 80° C. for 12 h. LCMS showed thecompound 6d was consumed and the desired MS was observed. The mixturewas concentrated. Compound 44a (133 mg, 288.56 umol, 99.96% yield) wasobtained as a white solid which was used for the next step withoutfurther purification. LCMS: (M+H⁺): 461.1.

Step 2. Preparation of7-((2R,3R,4S,5R)-5-((R)-(4-chlorophenyl)(hydroxy)methyl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)-1H-pyrrolo[2,3-d]pyrimidin-4(7H)-oneO-methyl oxime (44)

A mixture of compound 44a (133.00 mg, 288.56 umol, 1 eq.) in HCl/MeOH (4M, 2.00 mL, 27.72 eq.) was stirred at 25° C. for 1 h. LCMS showed thecompound 44a was consumed. The mixture was concentrated. The residue waspurified by prep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase:[water (0.04% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 10%-40%, 10 min).Compound 44 (28.44 mg, 65.98 umol, 22.87% yield, LCMS 97.6% purity) wasobtained as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=11.13-10.34(m, 1H), 8.12 (br s, 0.2H), 7.59-7.20 (m, 5H), 6.58 (br d, J=3.1 Hz,0.3H), 6.31-6.10 (m, 0.8H), 6.03-5.70 (m, 1H), 5.34-5.17 (m, 1H),4.85-4.70 (m, 2H), 4.39 (br s, 0.3H), 4.26 (br t, J=7.5 Hz, 0.5H), 4.02(br d, J=6.4 Hz, 0.4H), 3.95 (br d, J=6.8 Hz, 0.6H), 3.78-3.70 (m, 3H),1.30-1.17 (m, 3H); ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ=8.08 (br s, 0.2H),7.54-7.12 (m, 5H), 6.57 (d, J=3.5 Hz, 0.3H), 6.27 (d, J=3.4 Hz, 0.5H),5.91 (br d, J=8.2 Hz, 0.3H), 5.74 (d, J=8.2 Hz, 0.5H), 4.81-4.63 (m,1H), 4.35 (br d, J=8.3 Hz, 0.3H), 4.23 (d, J=8.1 Hz, 0.6H), 4.03 (br d.J=6.2 Hz, 0.3H), 3.96 (d, J=7.0 Hz, 0.5H), 3.77-3.64 (m, 3H), 1.19 (s,3H); LCMS: (M+H⁺): 421.1; LCMS purity 97.64%; HPLC purity: 98.24%.

Example 45.7-(((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(methoxyimino)-3H-pyrrolo[2,3-d]pyrimidin-7(4H)-yl)-3-methyltetrahydrofuran-2-yl)methoxy)quinolin-2(1H)-oneO-methyl oxime (45)

Step 1. Preparation of2-chloro-7-(((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)quinoline(45a)

To a solution of compound 19a (0.2 g, 588.63 umol, 1 eq.) and compoundInt-2 (158.58 mg, 882.94 umol, 1.5 eq.) in toluene (4 mL) was added2-(tributyl-phosphanylidene)acetonitrile (284.13 mg, 1.18 mmol, 2 eq.)under N₂ at 25° C. The mixture was stirred at 80° C. for 10 h. LC-MSshowed no compound 19a was remained. Several new peaks were shown onLC-MS and desired compound was detected. The reaction mixture wasconcentrated under reduced pressure to remove solvent. The residue waspurified by prep-TLC (SiO₂, Petroleum ether/Ethyl acetate=3:1) and basedon TLC (Plate 1 Petroleum ether/Ethyl acetate=3:1 R_(f)=0.21). Compound45a (220 mg, crude) was obtained as a white solid. LCMS: (M+H⁺): 501.1;TLC (Petroleum ether:Ethyl acetate=3:1) R_(f)=0.21.

Step 2. Preparation of7-(((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(methoxyimino)-3H-pyrrolo[2,3-d]pyrimidin-7(4H)-yl)-3-methyltetrahydrofuran-2-yl)methoxy)quinolin-2(H)-oneO-methyl oxime (45)

To a solution of compound 45a (0.22 g, 438.81 umol, 1 eq.) in t-BuOH (1mL) was added O-methylhydroxylamine hydrochloride (293.18 mg, 3.51 mmol,266.53 uL, 8 eq.) under N₂ at 25° C. The mixture was stirred at 100° C.for 12 h. LC-MS showed compound 1c was consumed completely and one mainpeak with desired MS was detected. The reaction mixture was concentratedunder reduced pressure to remove solvent. The residue was added sat. aq.NaHCO₃and extracted with DCM (5 mL×2) and EtOAc (5 mL×2). The organiclayer was washed with brine (10 mL×2), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by prep-HPLC (basic condition column: YMC-Actus Triart C18100*30 mm*5 um; mobile phase: water (0.04% NH₃.H₂O 10 mM NH₄HCO₃)-ACN B%: 20% -40%, 12 min). Compound 45 (57.41 mg, 114.87 umol, 26.18% yield,LCMS purity 96.54%) was obtained as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ=10.91 (br s, 0.6H), 10.55 (s, 0.3H), 9.84 (s, 1H), 7.46 (d,J=3.51 Hz, 0.7H), 7.16-7.26 (m, 0.8H), 7.13 (d, J=3.51 Hz, 0.5H),6.93-7.05 (m, 1.8H), 6.48-6.62 (m, 1.1H), 6.23 (d, J=3.51 Hz, 0.7H),5.90-6.11 (m, 1.3H), 5.31-5.46 (m, 1H), 4.92-5.07 (m, 1H), 4.22-4.43 (m,1H), 3.96-4.16 (m, 2.6H), 3.70 (d, J=10.09 Hz, 5.5H), 3.28 (br s, 1H),1.17-1.30 (m, 3H); ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ=7.51 (s, 0.5H),7.23-7.25 (m, 0.4H), 7.20-7.23 (m, 0.6H), 7.13 (d, J=3.51 Hz, 0.6H),7.06 (s, 0.4H), 7.04 (s, 0.5H), 6.93-6.98 (m, 1H), 6.55-6.62 (m, 1.2H),6.28 (d, J=3.51 Hz, 0.5H), 6.09 (s, 0.4H), 6.07 (s, 0.4H), 5.96 (d,J=7.89 Hz, 0.5H), 4.27 (d, J=7.89 Hz, 0.6H), 3.99-4.17 (m, 2.7H), 3.75(s, 1.6H), 3.69-3.72 (m, 4H), 3.68 (s, 2H), 1.19-1.29 (m, 3H); LCMS:(M+H⁺): 483.3. LCMS purity 96.54%; HPLC purity: 100.00%.

Example 46.7-((2R,3R,4S,5R)-5-((R)-(4-chlorophenyl)(hydroxy)methyl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)-1H-pyrrolo[2,3-d]pyrimidin-4(7H)-oneoxime hydrochloride (46)

Step 1. Preparation of(Z)-7-((3aR,4R,6R,6aR)-6-((R)-(4-chlorophenyl)(hydroxy)methyl)-2,2,6a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)1H-pyrrolo[2,3-d]pyrimidin-4(7H)-one oxime (46a)

A mixture of compound 26d (80 mg, 177.65 umol, 1 eq.) and hydroxylamine(11.74 mg, 177.65 umol, 2 mL, 50% purity, 1 eq.) in dioxane (2 mL) wasstirred at 100° C. for 12 h. LCMS showed the compound 26d was consumedand the desired MS was observed. The mixture was concentrated. Compound46a (79 mg, crude) was obtained as brown oil, which was used for nextstep without further purification. LCMS: (M+H⁺): 447.1.

Step 2. Preparation of(Z)-7-((2R,3R,4S,5R)-5-((R)-(4-chlorophenyl)(hydroxy)methyl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)-1H-pyrrolo[2,3-d]pyrimidin-4(7H)-oneoxime hydrochloride (46)

A mixture of compound 46a (79.00 mg, 176.78 umol, 1 eq.) in HCl/MeOH (4M, 2 mL, 45.25 eq.) was stirred at 25° C. for 0.5 h. LCMS showed thecompound if was consumed and the desired MS was observed. The mixturewas concentrated. The residue was purified by prep-HPLC (column: UniSil120*30*10 um; mobile phase: [water (0.05% HCl)-ACN]; B %; 5% -30%, 11min). Compound 46 (17.12 mg, 38.08 umol, 21.54% yield, LCMS 98.587%purity, HCl) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ=10.99 (br s, 1H), 8.26 (s, 1H), 7.83 (br d, J=3.1 Hz, 1H), 7.42-7.35(m, 2H), 7.33-7.26 (m, 2H), 6.87 (br s, 1H), 6.01 (d, J=8.1 Hz, 1H),4.77 (d, J=7.6 Hz, 1H), 4.32 (d, J=8.1 Hz, 1H), 3.98 (d, J=7.6 Hz, 1H),1.32-1.19 (m, 3H); ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ=8.28 (s, 1H), 7.79(d, J=3.7 Hz, 1H), 7.41-7.25 (m, 4H), 6.82 (d, J=3.7 Hz, 1H), 6.01 (d,J=8.1 Hz, 1H), 4.74 (d, J=7.5 Hz, 1H), 4.30 (d, J=8.1 Hz, 1H), 3.99 (d,J=7.5 Hz, 1H), 1.30-1.19 (m, 3H); LCMS: (M+H⁺): 407.1; LCMS purity98.590/6; HPLC purity: 99.35%.

Example 47.(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(3,4-dichlorophenyl)(hydroxy)methyl)-3-methyltetrahydrofuran-3,4-diol(47)

Step 1. Preparation of(R)-((3aR,4R,6R,6aR)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)(3,4-dichlorophenyl)methanol(47a)

To a solution of compound 37b (90 mg, 185.66 umol, 1 eq.) in dioxane (5mL) was added NH₃.H₂O (26.03 mg, 185.66 umol, 28.60 uL, 25% purity, 1eq.) at 25° C. The mixture was sealed and stirred at 100° C. for 12 h(30 psi). LC-MS showed compound 37b was consumed completely and one mainpeak with desired product was detected. The reaction mixture wasconcentrated under reduced pressure to remove solvent. Compound 47a (80mg, crude) was used into the next step without further purification as ayellow solid.

Step 2. Preparation of(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(3,4-dichlorophenyl)(hydroxy)methyl)-3-methyltetrahydrofuran-3,4-diol(47)

To a solution of Compound 47a (80 mg, 171.92 umol, 1 eq.) was addedHCl/MeOH (4 M, 4.26 mL, 99.07 eq.) at 0° C. The mixture was stirred at25° C. for 10 min. LC-MS showed no Compound 47a was remained. Severalnew peaks were shown on LC-MS and desired compound was detected. Thereaction mixture was concentrated under reduced pressure to removesolvent. The residue was added NH₃.H₂O to adjusted pH around 8. Theresidue was purified by prep-HPLC (basic condition column: WatersXbridge 150*25 5 u; mobile phase: [water (0.04% NH₃H₂O+10 mMNH₄HCO₃)-ACN]; B %: 15%-45%, 10 min). Compound 47 (29.83 mg, 69.48 umol,40.41% yield, LCMS purity 99.05%) was obtained as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ=8.04 (s, 1H), 7.61 (d, J=1.75 Hz, 1H), 7.51 (d,J=8.77 Hz, 1H), 7.42 (d, J=3.51 Hz, 1H), 7.38 (dd, J=8.33, 1.75 Hz, 1H),7.07 (br s, 2H), 6.55-6.64 (m, 2H), 5.85 (d, J=8.33 Hz, 1H), 5.27 (d,J=7.45 Hz, 1H), 4.78-4.86 (m, 2H), 4.43 (t, J=7.89 Hz, 1H), 4.01 (d,J=6.14 Hz, 1H), 1.18 (s, 3H); ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ=8.03 (s,1H), 7.58 (d, J=1.54 Hz, 1H), 7.50 (d, J=8.16 Hz, 1H), 7.34-7.41 (m,2H), 6.58 (d, J=3.53 Hz, 1H), 5.84 (d, J=8.16 Hz, 1H), 4.80 (d, J=6.39Hz, 1H), 4.41 (d, J=8.16 Hz, 1H), 4.00 (d, J=6.39 Hz, 1H), 1.18 (s, 3H);LCMS: (M+H⁺): 425.1. LCMS purity 99.05%; HPLC purity: 100.00%.

Example 48.(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(3,4-dichlorophenyl)(hydroxy)methyl)-3-methyltetrahydrofuran-3,4-diol,bisulfate (48)

To(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2-[(R)-(3,4-dichlorophenyl)-hydroxy-methyl]-3-methyl-tetrahydrofuran-3,4-diol(100 mg, 0.24 mmol) in IPA (5 mL) was sonicated at 50° C. to get a clearsolution and then was added the sulfuric acid (2.14 mL, 0.24 mmol) andagain sonicated at 50° C. for 5 mins. The mixture was allowed to coolslowly and solid obtained was centrifuged, washed with minimal amount ofwater and dried under high vacuum to give 95 mg of needle like crystals;m.p. 216-219° C. ¹H NMR (500 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.65 (d,J=3.7 Hz, 1H), 7.60 (d, J=1.9 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.37 (dd,J=1.9, 8.3 Hz, 1H), 6.79 (d, J=3.6 Hz, 1H), 6.24 (br s, 1H), 5.94 (d,J=8.2 Hz, 1H), 5.33 (br s, 1H), 4.90 (br s, 1H), 4.80 (d, J=7.2 Hz, 1H),4.44-4.33 (m, 1H), 3.98 (d, J=7.2 Hz, 1H), 1.25 (s, 3H).

Example 49.(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(benzo[d][1,3]dioxol-5-ylmethyl)-3-methyltetrahydrofuran-3,4-diol(49)

Step 1. Preparation of benzo[d][1,3]dioxol-5-yl((3aS,4S,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanone(49a)

To a mixture of compound 26b (1 g, 2.52 mmol, 1 eq.) in THF (10 mL) wasadded compound Int-7 (0.5 M, 15.12 mL, 3 eq.) at 25° C. under N₂. Themixture was stirred at 25° C. for 0.5 h under N₂. TLC showed thecompound 26b was consumed. The mixture was quenched by saturatedNaHCO₃solution (30 mL). The mixture was extracted with EtOAc (10 mL×3).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate=100/1 to 30/1). Compound 49a (900 mg, 1.97mmol, 78.00% yield) was obtained as a yellow solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ=8.69 (s, 1H), 8.07 (d, J=3.5 Hz, 1H), 7.79 (dd, J=1.8,7.9 Hz, 1H), 7.61 (d, J=1.8 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 6.71 (d,J=3.9 Hz, 1H), 6.63 (d, J=0.9 Hz, 1H), 6.10 (s, 2H), 5.60 (s, 1H), 4.64(d, J=1.3 Hz, 1H), 1.82 (s, 3H), 1.46 (s, 3H), 1.34 (s, 3H); TLC (SiO₂,petroleum ether/ethyl acetate=2/1): R_(f)=0.7.

Step 2. Preparation of(R)-benzo[d][1,3]dioxol-5-yl((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(49b)

To a mixture of compound 49a (200 mg, 436.81 umol, 1 eq.) in toluene (2mL) was added DIBAL-H (1 M, 873.62 uL, 2 eq.) at −70° C. under N₂. Themixture was stirred at −70° C. for 0.5 h under N₂. TLC showed thecompound 49a was consumed. The mixture was quenched by water (0.5 mL),15% NaOH solution (0.5 mL), water (0.5 mL) and the mixture was stirredfor 10 min. The mixture was dried over MgSO₄, filtered and concentrated.The residue was purified by prep-TLC (SiO₂, petroleum ether/ethylacetate=1/1). Compound 49b (190 mg, 413.15 umol, 94.58% yield) wasobtained as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.67 (s,1H), 7.33 (d, J=3.8 Hz, 1H), 6.93 (d, J=1.6 Hz, 1H), 6.89-6.84 (m, 1H),6.79-6.74 (m, 1H), 6.67 (d, J=3.7 Hz, 1H), 6.24 (d, J=2.4 Hz, 1H), 5.95(s, 2H), 4.73 (dd, J=2.8, 8.7 Hz, 1H), 4.67 (d, J=2.3 Hz, 1H), 4.15-4.09(m, 1H), 2.31 (d, J=2.8 Hz, 1H), 1.86 (s, 3H), 1.68 (s, 3H), 1.44 (s,3H); TLC (SiO₂, petroleum ether/ethyl acetate=1/1): R_(f)=0.4.

Step 3. Preparation ofO—((R)-benzo[d][1,3]dioxol-5-yl((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)S-methyl carbonodithioate (49c)

A mixture of compound 49b (150 mg, 326.17 umol, 1 eq.), CS₂ (1.74 g,22.83 mmol, 1.38 mL, 70 eq.) and MeI (3.24 g 22.83 mmol, 1.42 mL, 70eq.) in THF (3 mL) was stirred at 0° C. for 0.5 h under N₂. NaH (27.40mg, 684.96 umol, 60% purity, 2.1 eq.) was added at 0° C. under N₂. Themixture was stirred at 0° C. for 0.5 h. LCMS showed the compound 49b wasconsumed and the desired MS was observed. The mixture was quenched bysaturated NH₄Cl solution (10 mL), extracted with EtOAc (5 mL×3). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by prep-TLC (SiO₂, petroleumether/ethyl acetate=5/1). Compound 49c (160 mg, crude) was obtained as awhite solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.69 (s, 1H), 7.30 (br d,J=3.8 Hz, 2H), 6.74 (s, 1H), 6.69 (s, 2H), 6.51 (d, J=9.7 Hz, 1H),6.30-6.18 (m, 1H), 5.92 (s, 2H), 4.84 (s, 1H), 4.60-4.48 (m, 1H), 2.58(s, 3H), 1.71 (s, 3H), 1.66 (s, 3H), 1.45 (s, 3H); LCMS: (M+H⁺): 550.1;TLC (SiO₂, petroleum ether/ethyl acetate=5/1): R_(f)=0.5.

Step 4. Preparation of7-((3aR,4R,6R,6aR)-6-(benzo[d][1,3]dioxol-5-ylmethyl)-2,2,6a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (49d) and7-((3aR,4R,6R,6aR)-6-(benzo[d][1,3]dioxol-5-ylmethyl)-2,2,6a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (49e)

A mixture of compound 49c (150 mg, 272.70 umol, 1 eq.), Bu₃SnH (396.87mg, 1.36 mmol, 360.79 uL, 5 eq.) and AIBN (134.34 mg, 818.11 umol, 3eq.) in toluene (2 mL) was stirred at 120° C. for 0.5 h. LCMS showed thecompound 49c was consumed and the desired MS was observed. The mixturewas concentrated. The residue was purified by prep-TLC (SiO₂, petroleumether/ethyl acetate=3/1). Compound 49d (45 mg, 101.38 umol, 37.18%yield) was obtained as a white solid. Compound 1f (20 mg, crude) wasobtained as yellow oil. LCMS of cpd. 49d: (M+H⁺): 444.0; LCMS of cpd.49e: (M+H⁺): 410.0; TLC (SiO₂, petroleum ether/ethyl acetate=3/1): R_(f)(cpd. 1e)=0.4 & R_(f) (cpd. 1f)=0.3.

Step 5. Preparation of7-((3aR,4R,6R,6aR)-6-(benzo[d][1,3]dioxol-5-ylmethyl)-2,2,6a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(49f)

A mixture of compound 49d (45 mg, 101.38 umol, 1 eq.) in NH₃.H₂O (1.82g, 12.98 mmol, 2 mL, 25% purity, 128.06 eq.) and dioxane (2 mL) wasstirred at 100° C. for 12 h. TLC showed the compound 49d was consumed.The mixture was concentrated. The crude product was used for next stepwithout further purification. Compound 49f (43 mg, crude) was obtainedas a yellow solid. LCMS: (M+H⁺): 425.1; TLC (SiO₂, petroleum ether/ethylacetate=5/1): R_(f)=0.0.

Step 6. Preparation of(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(benzo[d][1,3]dioxol-5-ylmethyl)-3-methyltetrahydrofuran-3,4-diol(49)

A mixture of compound 49f (40 mg, 94.24 umol, 1 eq.) in HCl/MeOH (4 M, 2mL, 84.89 eq.) was stirred at 25° C. for 1 h. LCMS showed the compound49f was consumed. The mixture was concentrated. The residue was purifiedby prep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase: [water(0.04% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 5%-25%, 10 min). Compound 49(2.43 mg, 6.26 umol, 6.65% yield, LCMS 99.063% purity) was obtained as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ=8.04 (s, 1H), 7.44 (d, J=3.5Hz, 1H), 7.00 (br s, 2H), 6.75-6.67 (m, 2H), 6.66-6.59 (m, 2H), 5.97 (d,J=7.7 Hz, 1H), 5.88 (dd, J=0.8, 5.4 Hz, 2H), 5.33 (d, J=6.8 Hz, 1H),4.82 (s, 1H), 4.37 (t, J=7.3 Hz, 1H), 3.93 (dd, J=3.4, 10.7 Hz, 1H),2.88-2.72 (m, 2H), 1.25 (s, 3H); ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ=8.02(s, 1H), 7.42 (d, J=3.7 Hz, 1H), 6.73-6.57 (m, 4H), 5.95 (d, J=7.7 Hz,1H), 5.84 (d, J=3.7 Hz, 2H), 4.35 (d, J=7.7 Hz, 1H), 3.92 (dd, J=5.0,9.4 Hz, 1H), 2.82-2.72 (m, 2H), 1.25 (s, 3H); LCMS: (M+H⁺): 385.0; LCMSpurity 99.063%; HPLC purity: 100.00%.

Example 50.(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(3,4-dichlorobenzyl)-3-methyltetrahydrofuran-3,4-diol(50)

Step 1. Preparation ofO—((R)-((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)(3,4-dichlorophenyl)methyl)S-methylcarbonodithioate (50a)

To a solution of compound 37b (150 mg, 309.43 umol, 1 eq.) in THF (3 mL)was added CS₂ (1.65 g, 21.66 mmol, 1.31 mL, 70 eq.) and MeI (3.07 g,21.66 mmol, 1.35 mL, 70 eq.). The mixture was stirred at 0° C. for 10min. The mixture was added NaH (25.99 mg, 649.81 umol, 60% purity, 2.1eq.) and stirred at 0° C. for 0.5 h. LC-MS showed compound 37b wasconsumed. Several new peaks were shown on LC-MS and desired compound wasdetected. The reaction mixture was concentrated under reduced pressureto remove solvent. The residue was diluted with H₂O (15 mL) andextracted with EtOAc (15 mL×3). The combined organic layers were washedwith brine (25 mL×2), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by prep-TLC(SiO₂, Petroleum ether/Ethyl acetate=3/1) and based on TLC (Petroleumether/Ethyl acetate=3/1, R_(f)=0.61). The compound 50a (150 mg, 240.79umol, 77.82% yield, 92.29% purity) was obtain as a white solid. TLC(Petroleum ether: Ethyl acetate=3:1) R_(f)=0.61; LCMS1: (M+H⁺): 575.7;LCMS2: (M+H⁺): 575.8, LCMS purity 92.29%.

Step 2. Preparation of4-chloro-7-((3aR,4R,6R,6aR)-6-(3,4-dichlorobenzyl)-2,2,6a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine(50b) and7-((3aR,4R,6R,6aR)-6-(3,4-dichlorobenzyl)-2,2,6a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine(50c)

To a solution of compound 50a (70 mg, 121.75 umol, 1 eq.) in toluene (1mL) was added AIBN (6.00 mg, 36.53 umol, 0.3 eq.) and Bu₃SnH (220.00 mg,755.86 umol, 200.00 uL, 6.21 eq.) under N₂ at 25° C. The mixture wasstirred at 110° C. for 1 h. LC-MS showed no compound 50a was remained.Several new peaks were shown on LC-MS and desired compound 50b and 50cwere detected. The reaction mixture was concentrated under reducedpressure to remove solvent. The residue was purified by prep-TLC (SiO₂,Petroleum ether:Ethyl acetate=3:1) and based on TLC (Petroleumether:Ethyl acetate=3:1, R_(f) (cpd. 50b)=0.54, R_(f) (cpd. 50c)=0.21).Compound 50b (40 mg, crude) was obtained as a colourless oil. Compound50c (10 mg, crude) was obtained as a colourless oil. LCMS of cpd. 50b:(M+H⁺): 470.1; LCMS of cpd. 50c: (M+H⁺): 434.0, LCMS purity 79.33%.

Step 3. Preparation of7-((3aR,4R,6R,6aR)-6-(3,4-dichlorobenzyl)-2,2,6a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(50d)

To a solution of compound 50b (40 mg, 85.33 umol, 1 eq.) in dioxane (3mL) was added NH₃.H₂O (2.73 g, 19.47 mmol, 3 mL, 25% purity, 228.19 eq.)at 25° C. The mixture was sealed and stirred at 100° C. for 10 h (30psi). LC-MS showed compound 50b was consumed completely and one mainpeak with desired mass was detected. The reaction mixture wasconcentrated under reduced pressure to remove solvent. Compound 50d (40mg, crude) was used into the next step without further purification as ayellow solid. LCMS: (M+H⁺): 449.3.

Step 4. Preparation of(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(3,4-dichlorobenzyl)-3-methyltetrahydrofuran-3,4-diol(50)

To a solution of compound 50d (80 mg, 178.04 umol, 1 eq.) was addedHCl/MeOH (4 M, 4.64 mL, 104.24 eq.) and stirred at 25° C. for 5 min.LC-MS showed no compound 50d was remained. Several new peaks were shownon LC-MS and desired compound 50 was detected. The reaction mixture wasadded NH₃.H₂O adjusted pH around 8 and concentrated under reducedpressure to remove solvent at 25° C. The residue was purified byprep-HPLC (basic condition: column: Waters Xbridge 150*25 5 u; mobilephase: [water (0.04% NH₃H₂O+10 mM NH₄HCO₃)-CAN]; B %: 10%-40%, 10 min).Compound 50 (20.04 mg, 48.84 umol, 27.43% yield, 99.75% purity) wasobtained as a white solid. LCMS1: (M+H⁺): 409.3; ¹H NMR (400 MHz,DMSO-d₆) δ=8.05 (s, 1H), 7.42-7.49 (m, 3H), 7.17 (dd, J=8.38, 1.98 Hz,1H), 7.00 (s, 2H), 6.63 (d, J=3.75 Hz, 1H), 5.98 (d, J=7.72 Hz, 1H),5.37 (d, J=6.84 Hz, 1H), 4.88 (s, 1H), 4.42 (t, J=7.39 Hz, 1H), 4.00(dd, J=11.25, 3.09 Hz, 1H), 2.93-3.02 (m, 1H), 2.84-2.91 (m, 1H), 1.27(s, 3H); ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ=8.03 (s, 1H), 7.37-7.45 (m,3H), 7.16 (dd, J=8.27, 1.87 Hz, 1H), 6.63 (d, J=3.53 Hz, 1H), 5.96 (d,J=7.94 Hz, 1H), 4.39 (d, J=7.94 Hz, 1H), 3.99 (dd, 0.1=10.80, 3.53 Hz,1H), 2.78-3.00 (m, 2H), 1.27 (s, 3H); LCMS2: (M+H⁺): 409.0, LCMS purity99.75%; HPLC purity: 100.00%.

Example 51.(2R,3S,4R,5R)-2-(3,4-dichlorobenzyl)-3-methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(51)

To a solution of compound 50c (20 mg, 46.05 umol, 1 eq.) was addedHCl/MeOH (4 M, 1.20 mL, 104.24 eq.) and stirred at 25° C. for 5 min.LC-MS showed no compound 50c was remained. Several new peaks were shownon LC-MS and desired compound 51 was detected. The reaction mixture wasadded NH₃.H₂O adjusted pH around 8 and concentrated under reducedpressure to remove solvent at 25° C. The residue was purified byprep-HPLC (basic condition: column: Waters Xbridge 150*25 5 u; mobilephase: [water (0.04% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 15%-45%, 10 min).Compound 51 (2.31 mg, 5.44 umol, 11.82% yield, 92.89% LCMS purity) wasobtained as a white solid. LCMS1: (M+H⁺): 394.3; ¹H NMR (400 MHz,DMSO-d₆) δ=9.03 (s, 1H), 8.81 (s, 1H), 8.00 (d, J=3.75 Hz, 1H),7.41-7.47 (m, 2H), 7.18 (dd, J=8.38, 1.98 Hz, 1H), 6.76 (d, J=3.75 Hz,1H), 6.16 (d, J=7.94 Hz, 1H), 5.48 (d, J=6.84 Hz, 1H), 4.98 (s, 1H),4.50 (t, J=7.28 Hz, 1H), 4.07 (dd, J=11.14, 3.20 Hz, 1H), 2.96-3.08 (m,1H), 2.83-2.95 (m, 1H), 1.30 (s, 3H); ¹H NMR (400 MHz, DMSO-d₆+D₂O)δ=8.99 (s, 1H), 8.76 (s, 1H), 7.90 (d, J=3.95 Hz, 1H), 7.40 (d, J=7.89Hz, 1H), 7.37 (s, 1H), 7.15 (d, J=8.33 Hz, 1H), 6.77 (d, J=3.51 Hz, 1H),6.12 (d, J=8.33 Hz, 1H), 4.47 (d, J=7.89 Hz, 1H), 4.02-4.08 (m, 1H),2.88-2.95 (m, 1H), 1.29 (s, 3H); LCMS2: (M+H⁺): 394.0, LCMS purity92.89%; HPLC purity: 95.16%.

Example 52.(2R,3S,4R,5R)-2-(benzo[d][1,3]dioxol-5-ylmethyl)-3-methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(52)

A mixture of 49e (20 mg, 48.85 umol, 1 eq.) in HCl/MeOH (4 M, 2 mL,163.77 eq.) was stirred at 25° C. for 0.5 h. LCMS showed the compound49e was consumed. The mixture was concentrated. The residue was purifiedby prep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase: [water(0.04% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 10%-40%, 10 min). Compound 52(5.25 mg, 14.08 umol, 28.83% yield, LCMS 99.078% purity) was obtained asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=9.02 (s, 1H), 8.80 (s, 1H),7.97 (d, J=3.7 Hz, 1H), 6.76 (d, J=3.7 Hz, 1H), 6.74-6.69 (m, 2H), 6.63(d, J=8.1 Hz, 1H), 6.15 (d, J=7.8 Hz, 1H), 5.88 (d, J=4.3 Hz, 2H), 5.43(br s, 1H), 4.93 (br s, 1H), 4.47 (d, J=7.7 Hz, 1H), 4.01 (dd, J=3.2,10.8 Hz, 1H), 2.93-2.76 (m, 2H), 1.28 (s, 3H); ¹H NMR (400 MHz,DMSO-d₆+D₂O) δ=8.99 (d, J=2.3 Hz, 1H), 8.75 (d, J=2.1 Hz, 1H), 7.87 (d,J=2.8 Hz, 1H), 6.79-6.74 (m, 1H), 6.71-6.58 (m, 3H), 6.11 (dd, J=2.3,7.8 Hz, 1H), 5.82 (br d, J=2.6 Hz, 2H), 4.43 (dd, J=2.8, 7.9 Hz, 1H),2.86-2.74 (m, 2H), 1.27 (br s, 3H); LCMS: (M+H⁺): 370.1; LCMS purity99.078%; HPLC purity: 100.00%.

Example 53.(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-2-(7-quinolyloxymethyl)tetrahydrofuran-3,4-diol(53)

Step 1. Preparation of[(3aR,4R,6R,6aR)-6-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methyl4-methylbenzenesulfonate (53a)

To a solution of TEA (0.12 mL, 0.88 mmol) and Tosyl chloride (112.2 mg,0.59 mmol) in DCM (15.0 mL) was added[(3aR,4R,6R,6aR)-6-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methanol (19a) (100.0 mg,0.29 mmol) and DMAP (35.9 mg, 0.29 mmol). The reaction mixture wasstirred at 35° C. for 1 h. LCMS showed the reaction was completed. Themixture was diluted with DCM (50.0 mL) and washed with brine (20.0mL×3), dried over Na₂SO₄, filtered and concentrated in vacuum to givecrude product which was purified silica gel column chromatography(DCM:MeOH=50:1 to afford[(3aR,4R,6R,6aR)-6-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methyl4-methylbenzenesulfonate (53a) (150.0 mg, 0.29 mmol, 99.1% yield. LCMS[M+H]: 494.1.

Step 2. Preparation of7-[[(3aR,4R,6R,6aR)-6-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[34-d][1,3]dioxol-4-yl]methoxy]quinoline(53b)

To a solution of[(3aR,4R,6R,6aR)-6-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methyl4-methylbenzenesulfonate (53a) (150.0 mg, 0.30 mmol) in DMF (10.0 mL)was added Cs₂CO₃ (296.8 mg, 0.91 mmol) and quinolin-7-ol (44.1 mg, 0.30mmol). The reaction mixture was stirred at 80° C. for 16 h under N₂. Thereaction mixture was concentrated in vacuum and diluted with EtOAc (10.0ml). The mixture was washed with brine (10.0 mL×2), dried over Na₂SO₄,filtered and concentrated in vacuum to give crude product which waspurified by pre-TLC (MeOH:DCM=1:15) to afford7-[[(3aR,4R,6R,6aR)-6-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methoxy]quinoline(53b) (30.0 mg, 0.06 mmol, 19.9% yield). LCMS [M+H]: 466.9.).

Step 3. Preparation of 7-[(3aR,4R,6R,6aR)-2,2,3a-trimethyl-4-(7-quinolyloxymethyl)-6,6a-dihydro-4H-furo-[3,4-d][1,3]dioxol-6-yl]pyrrolo[2,3-d]pyrimidin-4-amine(53c)

A solution of7-[[(3aR,4R,6R)-6-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methoxy]quinoline (30.0 mg, 0.06 mmol)in 1,4-Dioxane (5.0 mL) and Ammonium hydroxide (5.0 mL, 129.81 mmol) wasstirred at 120° C. for 18 h in a sealed tube. TLC (PE:EA=1:1, R_(f)=0.1)showed the reaction was completed. The reaction mixture was concentratedin vacuum to 7-[(3aR,4R,6R,6aR)-2,2,3a-trimethyl-4-(7-quinolyloxymethyl)-6,6a-dihydro-4H-furo-[3,4-d][1,3]dioxol-6-yl]pyrrolo[2,3-d]pyrimidin-4-amine(53c) (29.9 mg, 0.07 mmol) which was used to the next step directly.

Step 4. Preparation of(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-2-(7-quinolyloxymethyl)tetrahydrofuran-3,4-diol(53)

A mixture of7-[(3aR,4R,6R,6aR)-2,2,3a-trimethyl-4-(7-quinolyloxymethyl)-6,6a-dihydro-4H-furo-[3,4-d][1,3]dioxol-6-yl]pyrrolo[2,3-d]pyrimidin-4-amine (29.9 mg, 0.07mmol), Water (3.0 mL) and TFA (0.2 mL, 2.73 mmol) was stirred at 40° C.for 2 h. LCMS showed the reaction was completed. The reaction mixturewas purified by prep-HPLC, eluted with MeCN in H₂O (0.1% NH₃.H₂O) from10.0% to 95.0% to give(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-2-(7-quinolyloxymethyl)tetrahydrofuran-3,4-diol(Ex. 53) (3.0 mg, 0.007 mmol, 11.0% yield) as a white solid. LCMS [M+H]:408.2.). ¹H NMR (400 MHz, DMSO-d₆) δ 8.66 (s, 1H), 8.29 (s, 1H), 7.79(d, J=3.6 Hz 1H), 7.60 (d, J=8.4 Hz, 1H), 6.94-6.98 (m, 2H), 6.77 (d,J=3.2 Hz, 1H), 6.56 (s, 2H), 6.29 (d, J=8.4 Hz, 1H), 5.22-5.55 (m, 2H),4.48 (d, J=8.0 Hz, 1H), 4.21-4.29 (m, 3H), 2.64 (s, 3H), 1.31 (s, 3H).¹H NMR (400 MHz, DMSO-d₆+D₂O) 6 8.66 (s, 1H), 8.30 (s, 1H), 7.77 (d,J=3.2 Hz 1H), 7.63 (d, J=8.8 Hz, 1H), 6.97-6.99 (m, 2H), 6.78 (d, J=3.2Hz, 1H), 6.29 (d, J=7.6 Hz, 1H), 4.49 (d, J=8.0 Hz, 1H), 4.14-4.27 (m,3H), 2.65 (s, 3H), 1.32 (s, 3H).

Example 54.(2R,3S,4R,5R)-3-methyl-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-2-(7-quinolyloxymethyl)tetrahydrofuran-3,4-diol(54)

Step 1. Preparation of7-[[(3aR,4R,6R,6aR)-2,2,3a-trimethyl-6-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methoxy]quinoline(54a)

To a solution of7-[[(3aR,4R,6R,6aR)-6-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methoxy]quinoline (53b)(80.0 mg, 0.17 mmol) in THF (5.0 mL) was addedTetrakis(triphenylphosphine)palladium (19.8 mg, 0.02 mmol), Dimethylzinc(1.71 mL, 1.71 mmol). The reaction mixture was stirred at 80° C. for 4 hunder N₂. LCMS showed the reaction was completed. The reaction mixturewas poured into NH₄Cl aqueous (20.0 mL) and extracted with EA (30.0mL×3), dried over Na₂SO₄, filtered, concentrated in vacuum to give crudeproduct which was purified by silica gel column chromatography(PE:EA=10:1) to afford7-[[(3aR,4R,6R,6aR)-2,2,3a-trimethyl-6-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methoxy]quinoline(54a) (72.0 mg, 0.15 mmol, 88.5% yield) as a solid. LCMS [M+H]: 447.2.

Step 2. Preparation of give(2R,3S,4R,5R)-3-methyl-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-2-(7-quinolyloxymethyl)tetrahydrofuran-3,4-diol(54)

A mixture of7-[[(3aR,4R,6R,6aR)-2,2,3a-trimethyl-6-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methoxy]quinoline(54a) (72.0 mg, 0.15 mmol), Water (0.60 mL) and TFA (0.38 mL) wasstirred at 40° C. for 2 h. LCMS showed the reaction was completed. Thereaction mixture was purified by prep-HPLC, eluted with MeCN in H₂O(0.1% NH₃.H₂O) from 10.0% to 95.0% to give(2R,3S,4R,5R)-3-methyl-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-2-(7-quinolyloxymethyl)tetrahydrofuran-3,4-diol(Ex. 54) (26.0 mg, 0.06 mmol, 42.1% yield) as a white solid. LCMS [M+H]:407.2. ¹H NMR (400 MHz, DMSO-d₆) δ 8.83-8.84 (d, J=2.4 Hz, 1H), 8.67 (s,1H), 8.30 (d, J=8 Hz, 1H), 7.92 (d, J=9.2 Hz, 1H), 7.83 (d, J=4 Hz, 1H),7.49 (s, 1H), 7.34-7.41 (m, 2H), 6.78 (d, J=3.6 Hz, 1H), 6.31 (d, J=8.4Hz, 1H), 6.06 (d, J=6 Hz, 2H), 4.51-4.53 (m, 1H), 4.34-4.36 (m, 2H),4.26 (d, J=4.0 Hz, 1H), 2.65 (d, J=10.2 Hz, 3H), 1.34 (s, 3H). ¹H NMR(400 MHz, DMSO-d₆+D₂O) δ 8.83 (s, 1H), 8.67 (s, 1H), 8.30-8.32 (m, 1H),7.93-7.96 (m, 1H), 7.80 (d, J=3.2 Hz, 1H), 7.49 (s, 1H), 7.37-7.43 (m,2H), 6.78 (d, J=3.2 Hz, 1H), 6.30-6.33 (m, 1H), 4.53 (d, J=8.0 Hz, 1H),4.32-4.38 (m, 2H), 4.28 (s, 1H), 2.67 (s, 3H), 1.33 (s, 3H).

Example 55. (2R,3S,4R,5R)-2-[(2-amino-3-bromo-7-quinolyl)oxymethyl]-3-methyl-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(55)

Step 1. Preparation of[(3aR,4R,6R,6aR)-2,2,3a-trimethyl-6-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methyl4-methylbenzenesulfonate (55a)

To a solution of TEA (0.46 mL, 3.29 mmol) and Tosyl chloride (417.88 mg,2.19 mmol) in DCM (7.0 mL) was added[(3aR,4R,6R,6aR)-2,2,3a-trimethyl-6-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methanol(10a) (350.0 mg, 1.10 mmol) and DMAP (66.9 mg, 0.55 mmol). The reactionmixture was stirred at 40° C. for 1 h. TLC (EA:PE=1:1, R_(f)=0.5) showedthe reaction was completed. The mixture was diluted with DCM (50.0 mL)and washed with brine (20.0 mL×3), dried over Na₂SO₄, filtered andconcentrated in vacuum to give crude product which was purified bysilica gel column chromatography (EA:PE=1:2) to afford[(3aR,4R,6R,6aR)-2,2,3a-trimethyl-6-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methyl4-methylbenzenesulfonate (55a) (476.0 mg, 0.98 mmol, 89.4% yield) as awhite solid. LCMS [M+H]: 474.1.

Step 2. 7-[[(3aR,4R,6R,6aR)-2,2,3a-trimethyl-6-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methoxy]-3-bromo-2-chloro-quinoline(55b)

To a solution of[(3aR,4R,6R,6aR)-2,2,3a-trimethyl-6-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methyl4-methylbenzenesulfonate (55a) (175.0 mg, 0.37 mmol) in DMF (2.0 mL) wasadded Cs₂CO₃ (361.2 mg, 1.11 mmol) and 2-bromo-3-chloro-quinolin-7-ol(Int-9) (95.5 mg, 0.37 mmol). The reaction mixture was stirred at 80° C.for 16 h under N₂. LCMS showed the reaction was completed. The reactionmixture was concentrated in vacuum and diluted with EtOAc (10.0 ml). Themixture was washed with brine (10.0 mL×2), dried over Na₂SO₄, filteredand concentrated in vacuum to give crude product which was purified bysilica gel column chromatography (EA:PE=1:1) to afford7-[[(3aR,4R,6R,6aR)-2,2,3a-trimethyl-6-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methoxy]-3-bromo-2-chloro-quinoline(55b) (75.0 mg, 0.10 mmol, 27.2% yield) as a white solid. LCMS [M+H]:559.1.

Step 3. Preparation of7-[[(3aR,4R,6R,6aR)-2,2,3a-trimethyl-6-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methoxy]-3-bromo-quinolin-2-amine(55c)

A solution of7-[[(3aR,4R,6R,6aR)-2,2,3a-trimethyl-6-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methoxy]-3-bromo-2-chloro-quinoline(55b) (95.0 mg, 0.17 mmol) in 1,4-Dioxane (1.0 mL) and Ammoniumhydroxide (2.8 mL, 73.26 mmol) was stirred at 140° C. for 68 h in asealed tube. LCMS showed the reaction was done and 26.0% of SM was left.The reaction mixture was concentrated in vacuum to give crude product7-[[(3aR,4R,6R,6aR)-2,2,3a-trimethyl-6-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methoxy]-3-bromo-quinolin-2-amine(55c) (110.0 mg) as a yellow solid which was used to the next stepdirectly. LCMS [M+H]: 540.1

Step 4. Preparation of (2R,3S,4R,5R)-2-[(2-amino-3-bromo-7-quinolyl)oxymethyl]-3-methyl-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(55)

A solution of7-[[(3aR,4R,6R,6aR)-2,2,3a-trimethyl-6-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methoxy]-3-bromo-quinolin-2-amine(110.0 mg, 0.20 mmol) in Water (1.0 mL) and TFA (1.5 mL, 20.19 mmol) wasstirred at 40° C. for 2 h. LCMS showed the reaction was completed. Thereaction mixture was purified by prep-HPLC, eluted with MeCN in H₂O(0.1% NH₃.H₂O) from 10.0% to 95.0% to give(2R,3S,4R,5R)-2-[(2-amino-3-bromo-7-quinolyl)oxymethyl]-3-methyl-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(Ex. 55) (11.1 mg, 0.02 mmol, 10.8% yield) as a white solid. LCMS [M+H]:500.1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.66 (s, 1H), 8.29 (s, 1H), 7.79 (d,J=3.6 Hz 1H), 7.60 (d, J=8.4 Hz, 1H), 6.94-6.98 (m, 2H), 6.77 (d, J=3.2Hz, 1H), 6.56 (s, 2H), 6.29 (d, J=8.4 Hz, 1H), 5.22-5.55 (m, 2H), 4.48(d, J=8.0 Hz, 1H), 4.21-4.29 (m, 3H), 2.64 (s, 3H), 1.31 (s, 3H). ¹H NMR(400 MHz, DMSO-d₆+D₂O) δ8.66 (s, 1H), 8.30 (s, 1H), 7.77 (d, J=3.2 Hz1H), 7.63 (d, J=8.8 Hz, 1H), 6.97-6.99 (m, 2H), 6.78 (d, J=3.2 Hz, 1H),6.29 (d, J=7.6 Hz, 1H), 4.49 (d, J=8.0 Hz, 1H), 4.14-4.27 (m, 3H), 2.65(s, 3H), 1.32 (s, 3H).

Example 56.(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-(4-chloro-3-methylphenyl)(hydroxy)methyl)-3-methyltetrahydrofuran-3,4-diol(56)

Example 56, an off-white solid, was prepared with a similar synthesis ofEx. 26 except for substituting 4-chlorobenzenemagnesium bromide withInt-8 in step 3. ¹H NMR (500 MHz, Methanol-d₄) δ 8.11 (s, 1H), 7.40 (s,1H), 7.30 (m, 2H), 7.27 (d, J=3.7 Hz, 1H), 6.60 (d, J=3.6 Hz, 1H), 5.85(d, J=7.9 Hz, 1H), 5.01 (d, J=3.6 Hz, 1H), 4.67 (d, J=7.9 Hz, 1H), 4.37(d, J=3.7 Hz, 1H), 2.36 (s, 3H), 1.17 (s, 3H). LCMS (M+H⁺):404.96/406.9.

Example 57.(2R,3S,4R,5R)-2-((R)-(4-chloro-3-methylphenyl)hydroxy)methyl)-3-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(57)

Step 1. Preparation of(R)-[(3aR,4R,6R,6aR)-2,2,3a-trimethyl-6-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]-(4-chloro-3-methyl-phenyl)methanol(57b)

A 4 mL vial with septum containing(R)-[(3aR,4R,6R,6aR)-6-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]-(4-chloro-3-methyl-phenyl)methanol(57a) (64 mg, 0.14 mmol) and palladium; triphenylphosphane (8.02 mg,0.01 mmol) under nitrogen was charged with THF (1 mL) and purged withnitrogen for 10 min. The vial was then charged with Dimethylzinc (0.3mL, 0.61 mmol) and heated at 70° C. for 3 h. Complete by LCMS. Thereaction mixture was quenched by dropwise addition of sat. NaHCO₃ (5drops) at rt under nitrogen with vigorous stirring. The reaction mixturewas diluted with water and extracted with EtOAc three times. The organiclayers were combined, washed with brine, dried over Na₂SO₄ and filtered.The filtrate was concentrated under reduced pressure and purified on a12 g silica gel column chromatography using hexane/EtOAc (0→85%,wet-loaded in DCM) to yield(R)-[(3aR,4R,6R,6aR)-2,2,3a-trimethyl-6-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]-(4-chloro-3-methyl-phenyl)methanol(57b) (27 mg, 0.0608 mmol, 44.1% yield) as a white solid. LCMS M+HFound: 443.69/444.01, ¹H NMR (500 MHz, Chloroform-d₃) δ 8.81 (s, 1H),7.28 (m, 2H), 7.16 (d, J=8.2 Hz, 1H), 6.22 (m, 1H), 4.78 (t, J=10.8 Hz,1H), 4.65 (m, 1H), 4.18 (d, J=8.3 Hz, 1H), 2.94 (s, 1H), 2.36 (s, 3H),1.83 (s, 3H), 1.68 (s, 3H), 1.51 (s, 3H), 1.42 (s, 3H).

Step 2. Preparation of(2R,3S,4R,5R)-2-((R)-(4-chloro-3-methylphenyl)(hydroxy)methyl)-3-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(57)

To(R)-[(3aR,4R,6R,6aR)-2,2,3a-trimethyl-6-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-6,6a-dihydro-4H-furo[3,4-d][13]dioxol-4-yl]-(4-chloro-3-methyl-phenyl)methanol(57b) (27 mg, 0.06 mmol) in Methanol (1 mL) were added a few drops ofconc. HCl at 0° C. The reaction was stirred at rt. LCMS showed noremaining starting material and the reaction was concentrated underreduced pressure. The crude was diluted with EtOAc, cooled to 0° C. andcarefully neutralized with sat. aq. NaHCO₃. The organic layer wasseparated and the aqueous was extracted with EtOAc twice. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under vacuum. The crude was purified on a 12 g silica gelcolumn using CH₂Cl₂/CH₂Cl₂:MeOH:NH₃ (0 to 60% of solvent B) to give(2R,3S,4R,5R)-2-[(R)-(4-chloro-3-methyl-phenyl)-hydroxy-methyl]-3-methyl-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(13.8 mg, 0.03417 mmol, 57% yield) as an off-white solid. LCMS M+H+:403.76/404.01. ¹H NMR (500 MHz, DMSO-d₆) δ 8.64 (s, 1H), 7.85 (d, J=3.8Hz, 2H), 7.33 (d, J=2.0 Hz, 1H), 7.25 (d, J=8.2 Hz, 2H), 7.21 (dd,J=2.0, 8.5 Hz, 1H), 6.76 (d, J=3.7 Hz, 2H), 6.06 (d, J=8.2 Hz, 2H), 5.89(d, J=4.6 Hz, 1H), 5.29 (d, J=6.9 Hz, 2H), 4.83 (s, 1H), 4.76 (dd,J=4.7, 7.1 Hz, 1H), 4.43 (t, J=7.5 Hz, 1H), 4.00 (d, J=7.1 Hz, 1H), 2.65(s, 3H), 2.23 (s, 3H), 1.26 (s, 3H).

Example 58.(2R,3S,4R,5R)-2-((R)-(3,4-dichlorophenyl)(hydroxy)methyl)-3-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(58)

Example 58, a white solid, was prepared with a similar synthesis of Ex.57 except for substituting 57a with 37b in step 1. ¹H NMR (500 MHz,Methanol-d4) δ 8.65 (s, 1H), 7.67 (d, J=3.8 Hz, 1H), 7.61 (d, J=2.0 Hz,1H), 7.43 (d, J=8.4 Hz, 1H), 7.37 (dd, J=2.0, 8.4 Hz, 1H), 6.75 (d,J=3.7 Hz, 1H), 6.07 (d, J=7.9 Hz, 1H), 4.98 (d, J=5.0 Hz, 1H), 4.69 (d,J=7.9 Hz, 1H), 4.29 (d, J=5.0 Hz, 1H), 2.73 (s, 3H), 1.27 (s, 3H).

Example 64.(2R,3S,4R,5R)-2-[[4-chloro-2-(hydroxymethyl)phenyl]methyl]-3-methyl-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol (64)

Step 1. Preparation of[(3aS,4S,6R,6aR)-6-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-chloro-phenyl]methanone(64a)

To a solution of(2-bromo-5-chloro-phenyl)methoxy-tert-butyl-dimethyl-silane (8.46 g,25.2 mmol) in dry THF (208 mL) was added n-BuLi (12.6 mL, 20.2 mmol) at-78° C. and stirred for 5 min under N₂. 26b (4.0 g, 10.1 mmol) in dryTHF (10 mL) was added and stirred at -78° C. for 5 min. TLC (PE:EA=3:1,R_(f)=0.5) showed the reaction was complete. The reaction mixture waspoured into NH₄Cl aqueous and extracted with EA (300 mL×3), and thesolvent was concentrated under reduced pressure to give a crude productwhich was purified by silica gel column chromatography (PE:EA=5:1) togive 64a (3.09 g, 5.11 mmol, 50.7% yield) as a white solid. LCMS [M+H]:592.2

Step 2. Preparation of(R)-[(3aR,4R,6R,6aR)-6-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-chloro-phenyl]methanol(64b)

To a solution of 64a (3.0 g, 5.1 mmol) in Toluene (30 mL) was addedDIBAL-H (9.5 mL, 15.2 mmol) at -78° C. and stirred for 1 h under N₂. TLC(PE:EA=5:1, R_(f)=0.4) showed the reaction was complete. The reactionmixture was poured into NH₄Cl aqueous (300 mL) and extracted with EA(300 mL×3). The solvent was concentrated under reduced pressure to givea crude product which was purified by silica gel column chromatography(PE:EA=5:1) to give 64b (2.50 g, 4.12 mmol, 81.39% yield) as a whitesolid. LCMS [M+H]: 594.2

Step 3. Preparation ofO—[(R)-[(3aR,4R,6R,6aR)-6-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-chloro-phenyl]methyl]methylsulfanylmethanethioate (64c)

To a solution of 64b (400 mg, 0.67 mmol) in THF (10 mL) was added NaH(48.4 mg, 1.21 mmol) and stirred at 0° C. for 0.5 h. CS₂ (153.7 mg, 2.0mmol) was added and stirred at 0° C. for 0.5 h, then CH₃₁ (191 mg, 1.35mmol) was added and stirred at room temperature for 1 h. TLC (PE:EA=3:1,R_(f)=0.7) showed the reaction was complete. The reaction mixture waspoured into NH₄Cl aqueous (50 mL) and extracted with EA (50 mL×3). Thesolvent was concentrated under reduced pressure to give a crude productwhich was purified by silica gel column chromatography (PE:EA=20:1) togive 64c (267 mg, 0.38 mmol, 57% yield) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 8.93 (s, 1H), 8.14 (d, J=3.6 Hz, 1H), 7.52-7.65 (m, 3H),6.99 (d, J=3.6 Hz, 1H), 6.43-6.47 (m, 2H), 5.30 (s, 1H), 5.15 (d, J=14.8Hz, 1H), 4.59-4.65 (m, 2H), 2.88 (s, 3H), 1.99 (s, 3H), 1.83 (s, 3H),1.61 (s, 3H), 0.95 (s, 9H), 0.00 (s, 3H), -0.10 (s, 3H).

Step 4. Preparation of [2-[[(3aR,4R,6R,6aR)-6-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methyl]-5-chloro-phenyl]methoxy-tert-butyl-dimethyl-silane(64d)

To a solution of 64c (430 mg, 0.63 mmol) and AIBN (103 mg, 0.63 mmol) inToluene (20 mL) was added Tributyltin (183 mg, 0.63 mmol) under N₂, andthe reaction mixture was stirred at 115° C. for 18 h under N₂. LCMSshowed the reaction was complete. The reaction mixture was concentratedunder reduced pressure and purified by silica gel column chromatography(PE:EA=20:1) to give 64d (260 mg, 0.44 mmol, 70% yield) as a solid. LCMS[M+H]: 576.2

Step 5. Preparation of[2-[[(3aR,4R,6R,6aR)-2,2,3a-trimethyl-6-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methyl]-5-chloro-phenyl]methoxy-tert-butyl-dimethyl-silane(64e)

To a solution of 64d (150 mg, 0.26 mmol) andTetrakis(triphenylphosphine)palladium (30 mg, 0.03 mmol) in THF (10 mL)was added dimethylzinc (2.6 mL, 2.59 mmol), the reaction mixture wasstirred at 80° C. for 3 h. LCMS showed the reaction was complete. Thereaction was poured into NH₄Cl (50 mL) aqueous and extracted with EA (50mL×3). The solvent was concentrated under reduced pressure to give acrude product which was purified by reverse phase combi flash (neutralcondition) to give 64e (110 mg, 0.19 mmol, 74.5% yield) as a whitesolid. LCMS [M+H]: 558.2

Step 4. Preparation of(2R,3S,4R,5R)-2-[[4-chloro-2-(hydroxymethyl)phenyl]methyl]-3-methyl-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(64)

A solution of 64e (110 mg, 0.19 mmol) in Water (3 mL) and TFA (2 mL, 27mmol) was stirred at 40° C. for 1 h. LCMS showed the reaction wascomplete. The solvent was concentrated under reduced pressure andpurified by prep-HPLC (0.1% NH₃.H₂O), eluted with H₂O:CH₃CN from 90:10to 5:95 to give 64 (41 mg, 0.10 mmol, 51% yield) as a white solid. LCMS[M+H]: 404.1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (s, 1H), 7.90 (d, J=3.6Hz, 1H), 7.33 (s, 1H), 7.10 (d, J=1.2 Hz, 2H), 6.80 (d, J=3.6 Hz, 1H),6.10 (d, J=7.6 Hz, 1H), 5.40 (d, J=6.8 Hz, 1H), 5.21 (t, J=5.6 Hz, 1H),4.96 (s, 1H), 4.44-4.57 (m, 3H), 4.01-4.05 (m, 1H), 2.89-2.91 (m, 2H),2.66 (s, 3H), 1.33 (s, 3H). ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ 8.64 (s,1H), 7.87 (d, J=3.6 Hz, 1H), 7.33 (s, 1H), 7.11 (d, J=1.6 Hz, 2H), 6.81(d, J=7.6 Hz, 1H), 6.10 (d, J=7.6 Hz, 1H), 4.45-4.56 (m, 3H), 4.04 (d,J=6.4 Hz, 1H), 2.89 (d, J=6.8 Hz, 2H), 2.67 (s, 3H), 1.34 (s, 3H).

Example 66.(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((S)-(3,4-dichlorophenyl)(hydroxy)methyl)-3-methyltetrahydrofuran-3,4-diol(66)

Step 1. Preparation of[(S)-[(3aR,6R)-6-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]-(3,4-dichlorophenyl)methyl]4-nitrobenzoate (66a)

37b (18 mg, 0.04 mmol) was added to a solution of triphenylphosphine(23.89 mg, 0.09 mmol), diisopropyl azodicarboxylate (0.01 mL, 0.07 mmol)and 4-nitrobenzoic acid (9.3 mg, 0.06 mmol) in THF (1 mL) at 0° C. Theresulting solution was stirred at room temp 2 h then heated to 60° C.for 20 h. The mixture was diluted with water and EtOAc, the organicswere separated, washed with water, brine and dried over Na₂SO₄. Thesolvent was evaporated in vacuo, and the residue purified by flashcolumn chromatography (0-50% EtOAc in hexane) to give 66a (20 mg, 0.032mmol, 85% yield). LCMS [M+H]: 633.9

Step 2. Preparation of(R)-[(3aR,6R,6aR)-6-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]-(3,4-dichlorophenyl)methanol(66b)

Into a sealable tube was placed 66a (22 mg, 0.03 mmol) and ammoniumhydroxide (0.26 mL, 6.85 mmol) and 1,4-Dioxane (1 mL). The reaction washeated to 120° C. overnight, cooled to rt, and the solvent evaporated invacuo to give crude 66b (19 mg, 0.041 mmol, 119% yield) which was usedin the next step without further purification. LCMS [M+H]: 464.9

Step 3. Preparation of(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((S)-(3,4-dichlorophenyl)(hydroxy)methyl)-3-methyltetrahydrofuran-3,4-diol(66)

Into a vial was placed 66b (20 mg, 0.04 mmol) in THF (1 mL) followed by4N HCl (0.11 mL, 0.44 mmol) and the reaction was stirred overnight.Additional 4N HCl (0.11 mL, 0.44 mmol) added and the reaction wasstirred overnight. LCMS shows that the reaction was complete. Saturatedaqueous NaHCO₃was added until the solution was slightly basic. Themixture was extracted with DCM (3 mL), the organics were washed withbrine and dried over MgSO₄. The solvent was evaporated in vacuo, and theresidue was purified by flash column chromatography (0-40%EtOAc/hexanes) to afford 66 (7.2 mg, 0.017 mmol, 40% yield). LCMS [M+H]:424.9. 1H NMR (500 MHz, DMSO-d₆) δ 8.08 (s, 1H), 7.55 (d, J=2.0 Hz, 1H),7.53-7.43 (m, 2H), 7.36-7.23 (m, 2H), 7.14 (s, 2H), 6.59 (d, J=3.6 Hz,1H), 5.79 (d, J=8.1 Hz, 1H), 5.28 (d, J=7.1 Hz, 1H), 4.80 (d, J=8.6 Hz,1H), 4.77 (s, 1H), 4.47 (t, J=7.6 Hz, 1H), 3.98 (d, J=1.3 Hz, 1H), 1.45(s, 3H).

Example 67.(2R,3S,4R,5R)-3-methyl-2-[(3-methylimidazo[1,2-a]pyridin-7-yl)oxymethyl]-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(67)

Step 1. Preparation of[(3aR,4R,6R,6aR)-2,2,3a-trimethyl-6-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methanol(67a)

To a mixture of 19a (350 mg, 1.03 mmol) and Pd(PPh₃)₄ (119 mg, 0.10mmol) in THF (10 mL) was added Dimethylzinc (983.2 mg, 10.30 mmol)dropwise under N₂ atmosphere. The reaction was stirred at 80° C. for 3hours. TLC (PE:EA=10:1) showed the reaction was complete. The mixturewas poured into NH₄Cl aqueous (30 mL) and extracted with EA (30 mL×3).The organic phases were combined, dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by silica gel columnchromatography (PE:EA=50:1 to 5:1) to give 67a (300 mg, 0.81 mmol, 78%yield) as a white solid. LCMS: [M+H]: 320.2.

Step 2. Preparation of[(3aS,4S,6S,6aS)-2,2,3a-trimethyl-6-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]methyl4-methylbenzenesulfonate (67b)

To a solution of 67a (300 mg, 0.94 mmol), TEA (0.39 mL, 2.82 mmol) andDMAP (57.4 mg, 0.47 mmol) in DCM (20 mL) was added Tosyl chloride (358mg, 1.88 mmol) and the reaction mixture was stirred at 40° C. for 16 h.TLC (PE:EA=1:1, R_(f)=0.4) showed the reaction was complete. The mixturewas poured into H₂O/DCM washed by H₂O and brine, purified by silica gelchromatography (PE:EA=10:1 to 2:1) to afford (67b) (220 mg, 0.44 mmol,46.5% yield) as a white solid. LCMS: [M+H]: 474.1.

Step 3. Preparation of4-methyl-7-[(3aR,4R,6R,6aR)-2,2,3a-trimethyl-4-[(3-methylimidazo[1,2-a]pyridin-7-yl)oxymethyl]-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-6-yl]pyrrolo[2,3-d]pyrimidine (67d)

To a solution of 67b (60 mg, 0.13 mmol) in DMF (2 mL), were added 67c(prepared according to WO 2018/065365; 18.8 mg, 0.13 mmol) and Cs₂CO₃(124 mg, 0.38 mmol) and the reaction mixture was stirred at 80° C. for16 h under N₂ atmosphere. LCMS showed the reaction was complete. Thereaction was concentrated to dryness and the residue was taken up inEtOAc (10 mL) and the organic layer was washed with water (2×10 mL) thensaturated brine solution (1×20 mL). The organic layers were separated,dried (MgSO₄) and concentrated to give crude (67d) (60 mg, 0.11 mmol,89.5% yield). LCMS: [M+H]: 450.4.

Step 4. Preparation of(2R,3S,4R,5R)-3-methyl-2-[(3-methylimidazo[1,2-a]pyridin-7-yl)oxymethyl]-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(67)

To a solution of 67d (100 mg, 0.18 mmol) in water (3 mL) was added2,2,2-trifluoroacetic acid; TFA (3.43 mL, 44.5 mmol), and the mixturewas stirred at 25° C. for 90 min. LCMS showed the reaction was complete.The residue was purified by pre-HPLC, eluted with CH₃CN in H₂O (0.1%NH₄OH) from 5% to 95% to give(2R,3S,4R,5R)-3-methyl-2-[(3-methylimidazo[1,2-a]pyridin-7-yl)oxymethyl]-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(27 mg, 0.06 mmol, 37% yield) as a light yellow solid. LCMS: [M+H]:410.2.

¹H NMR (400 MHz, DMSO-d₆+D₂O): δ 8.66 (s, 1H), 8.25-8.27 (m, 1H),7.77-7.78 (m, 1H), 7.33-7.34 (m, 1H), 7.08-7.09 (m, 1H), 6.89-6.91 (m,1H), 6.77-6.78 (m, 1H), 6.27-6.29 (m, 1H), 4.48-4.50 (m, 1H), 4.27-4.29(m, 2H), 4.22-4.24 (m, 1H), 2.65 (s, 3H), 2.43 (s, 3H), 1.32 (s, 3H).

The examples listed below either were prepared, or can be prepared,using methods analogous to those described above.

TABLE B Synthesis of Additional Examples Ex. Synthesis similar #Structures to Ex. # Spectra Data 59

Ex. 10 and Ex. 47 1H NMR (500 MHz, Methanol-d4) δ 8.66 (s, 1H), 7.68 (d,J = 3.8 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H),6.75 (d, J = 3.7 Hz, 1H), 6.09 (d, J = 7.8 Hz, 1H), 5.01 (d, J = 4.5 Hz,1H), 4.62 (s, 1H, 4.39 (d, J = 4.5 Hz, 1H), 2.87 (h, J = 6.9 Hz, 1H),2.74 (s, 3H), 1.24 (s, 3H), 1.23 (d, 6H). LCMS (MH⁺): 398.0/398.9. 60

Ex. 10 and Ex. 47 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.85 (d, J =3.8 Hz, 1H), 7.54-7.38 (m, 2H), 7.29-7.14 (m, 2H), 6.75 (d, J = 3.7 Hz,1H), 6.07 (d, J = 8.1 Hz, 1H), 5.96 (d, J = 4.6 Hz, 1H), 5.29 (d, J =7.2 Hz, 1H), 4.84 (d, J = 3.3 Hz, 2H), 4.41 (t, J = 7.7 Hz, 1H), 4.03(d, J = 7.1 Hz, 1H), 2.63 (s, 3H), 1.24 (s, 3H). LCMS (MH⁺): 439.9. 61

Ex. 10 and Ex. 47 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.89 (d, J =3.6 Hz, 1H), 7.70 (d, J = 6.8 Hz, 2H), 7.35 (t, J = 9.9 Hz, 1H), 6.74(d, J = 3.6 Hz, 1H), 6.04 (d, J = 8.2 Hz, 1H), 5.98 (d, J = 4.6 Hz, 1H),5.33 (d, J = 7.0 Hz, 1H), 4.96-4.84 (m, 2H), 4.48 (t, J = 7.3 Hz, 1H),3.92 (d, J = 8.0 Hz, 1H), 2.63 (s, 3H), 1.31 (s, 3H). LCMS (MH⁺): 441.9.62

Ex. 10 and Ex. 47 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.87 (d, J =3.7 Hz, 1H), 7.59 (s, 4H), 6.76 (d, J = 3.7 Hz, 1H), 6.13-5.98 (m, 2H),5.30 (d, J = 6.5 Hz, 1H), 4.97-4.81 (m, 2H), 4.49-4.35 (m, 1H), 4.06 (d,J = 7.1 Hz, 1H), 2.64 (s, 3H), 1.25 (s, 3H). LCMS (MH⁺): 423.9. 63

Ex. 47 1H NMR (500 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.73 (t, J = 7.7 Hz,2H), 7.42 (d, J = 3.6 Hz, 1H), 7.41-7.34 (m, 1H), 7.06 (s, 2H), 6.57 (d,J = 3.6 Hz, 1H), 6.48 (s, 1H), 5.84 (d, J = 8.2 Hz, 1H), 5.25 (d, J =7.3 Hz, 1H), 4.95-4.85 (m, 1H), 4.79 (s, 1H), 4.46 (t, J = 7.7 Hz, 1H),3.97 (d, J = 7.0 Hz, 1H), 1.21 (s, 3H). LCMS (MH⁺): 442.9. 65

Ex. 64, Ex, 10. 1H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.44 (d, J =3.6 Hz, 1H), 7.34 (s, 1H), 7.11 (s, 2H), 7.00 (br, 2H), 6.63 (d, J = 3.6Hz, 1H), 5.95(d, J = 7.6 Hz, 1H), 5.33 (d, J = 7.2 Hz, 1H), 5.21 (t, J =5.2 Hz, 1H), 4.88 (s, 1H), 4.45-4.57 (m, 2H), 4.37 (t, J = 7.2 Hz, 1H),3.97 (t, J = 7.2 Hz, 1H), 2.85 (d, J = 6.8 Hz, 2H), 1.31 (s, 3H). LCMS(MH⁺): 405.12/407.1. 68

Ex. 67, Ex. 47 1H NMR (400 MHz, DMSO-d6 + D2O): δ 8.14-8.16 (m, 1H),8.05-8.06 (m, 1H), 7.39-7.40 (m, 1H), 7.18-7.19 (m, 1H), 7.00-7.01 (m,1H), 6.73-6.75 (m, 1H), 6.60-6.62 (m, 1H), 6.15-6.16 (m, 1H), 4.39-4.41(m, 1H), 4.16-4.19 (m, 3H), 2.41 (s, 3H), 1.30 (s, 3H). LCMS (MH⁺):411.2. 73

Ex. 46

Biochemical Assay Protocol

Compounds were solubilized and 3-fold diluted in 100% DMSO. Thesediluted compounds were further diluted in the assay buffer (50 mMTris-HCl, pH 8.5, 50 mM NaCl, 5 mM MgCl₂, 0.01% Brij35, 1 mM DTT, 1%DMSO) for 10-dose IC₅₀ mode at a concentration 10-fold greater than thedesired assay concentration. Standard reactions were performed in atotal volume of 50 μl in assay buffer, with histone H2A (5 μM final) assubstrate. To this was added the PRMT5/MEP50 complex diluted to providea final assay concentration of 5 nM and the compounds were allowed topreincubate for 15 to 20 minutes at room temperature. The reaction wasinitiated by adding S-[3H-methyl]-adenosyl-L-methionine (PerkinElmer) tofinal concentration of 1 μM. Following a 60 minutes incubation at 30°C., the reaction was stopped by adding 100 μL of 20% TCA. Each reactionwas spotted onto filter plate (Multi Screen FB Filter Plate, Millipore),and washed 5 times with PBS buffer, Scintillation fluid was added to thefilter plate and read in a scintillation counter. IC₅₀ values weredetermined by fitting the data to the standard 4 parameters with HillSlope using GraphPad Prism software.

Cellular Assay Protocol

Cell Treatment and Western Blotting for Detecting Symmetric Di-MethylArginine (sDMA) and Histone H3R8 Dimethyl Symmetric (H3R8me2s) Marks

Initial Compounds Screening in A549 Cells:

Compounds were dissolved in DMSO to make 10 mM stock and further dilutedto 0.1, and 1 mM. A549 cells were maintained in PRMI 1640 (CorningCellgro, Catalog #: 10-040-CV) medium supplemented with 10% v/v FBS (GEHealthcare, Catalog #: SH30910.03). One day before experiment, 1.25×10⁵cells were seeded in 6 well plate in 3 mL medium and incubatedovernight. The next day, medium was changed and 3 uL of compoundsolution was added (1:1,000 dilution, 0.1 and 1 uM final concentration;DMSO concentration: 0.1%), and incubated for 3 days. Cells incubatedwith DMSO was used as a vehicle control. Cells were washed once withPBS, trypsinized in 150 uL 0.25% Trypsin (Corning, Catalog #:25-053-CI), neutralized with 1 mL complete medium, transferred tomicroCentrifuge tubes and collected. Cell pellet was then resuspended in15 uL PBS, lysed in 4% SDS, and homogenized by passing throughhomogenizer column (Omega Biotek, Catalog #: HCR003). Total proteinconcentrations were determined by BCA assay (ThermoFisher Scientific,Catalog #: 23225). Lysates were mixed with 5× Laemmli buffer and boiledfor 5 min. Forty ug of total protein was separated on SDS-PAGE gels(Bio-Rad, catalog #: 4568083, 4568043), transferred to PVDF membrane,blocked with 5% dry milk (Bio-Rad, Catalog #: 1706404) in TBS with 0.1%v/v Tween 20 (TBST) for 1 hour at room temperature (RT), and incubatedwith primary antibodies (sDMA: Cell signaling, Catalog #: 13222,1:3,000; H3R8me2s: Epigentek, Catalog #: A-3706-100, 1:2,000; f3-Actin:Abcam, Catalog #: ab8227, 1:10,000) in 5% dry milk in TBST at 4° C. forovernight. The next day, membranes were washed with TBST, 5×5 min, andincubated with HRP conjugated seconded antibody (GE Healthcare; Catalog#: NA934-1ML: 1:5,000) for 2 hours at RT, followed by 5×5 min washeswith TBST, and incubation with ECL substrates (Bio-Rad, Catalog #:1705061, 1705062). Chemiluminescent signal was captured with FluochemHD2 imager (Proteinsimple) and analyzed by ImageJ.

To determine enzyme inhibition IC₅₀ values using Western Blot analysis,Granta cells were seeded at density of 5×10⁵ cells/mL in 3 mL medium(PRMI+10% v/v FBS). Nine-point 3-fold serial dilutions of compound wereadded to cells (3 ul, 1:1,000 dilution, DMSO concentration was 0.1%;final top concentration was 10 or 1 uM, depending on compounds potency)and incubated for 3 days. Cells incubated with DMSO was used as avehicle control. Cells were harvested and subjected to western blotanalysis as described above. SmD3me2s and H3R8me2s bands were quantifiedby ImageJ. Signals were normalized to f3-Actin and DMSO control. IC₅₀values were calculated using Graphpad Prism.

Cell Proliferation Assay to Determine IC₅₀ on Granta-519 Cells

Granta-519 cells were maintained in PRMI 1640 (Corning Cellgro, Catalog#: 10-040-CV) medium supplemented with 10% v/v FBS (GE Healthcare,Catalog #: SH30910.03). Compounds were dissolved in DMSO to make 10 mMstocks and stored at −20° C. Nine-point, 3-fold serial dilutions weremade with DMSO with top concentration at 1 mM (working stocks).

On day of experiment, compound working stocks were further diluted at1:50 with fresh medium in 96 well plate, and 10 μL of diluted drugs wereadded to a new 96 well plate for proliferation assay. Cells growing atexponential phase were spun down at 1500 rpm for 4 min and resuspend infresh medium to reach a density of 0.5×10⁶ cells/ml. 200 ul of cellswere added to 96 well plate containing diluted drugs and incubated for 3days. DMSO was used a vehicle control.

One day 3, 10 μL of Cell Counting Kit-8 (CCK-8, Jojindo, CK04-13)solution was added to a new 96 well plate. Cells incubated with drugsfor 3 days were resuspended by pipetting up and down, and 100 μL ofcells were transferred to 96 well plate containing CCK-8 reagent tomeasure viable cells. Plates were incubated in CO2 incubator for 2 hoursand OD450 values were measured with a microplate reader (iMarkmicroplate reader, Bio-Rad).

For re-plating, compound working stocks were diluted at 1:50 with freshmedium and 10 μL of diluted drugs were added to a new 96 well plate.Cells from Day 3 plate (50 ul) were added to 96 well plate containingfresh drug and additional 150 μL of fresh medium was added to reach 200μL volume. Plate was returned to CO2 incubator and incubated for 3 moredays. Viable cells measurement and re-plating were repeated on day 6,and the final viable cells measurement was taken on day 10.

Percentage of viable cells, relative to DMSO vehicle control, werecalculated and plotted in Graphpad Prism ([Inhibitor] vs. normalizedresponse−Variable slope) to determine proliferation IC₅₀ values on day10.

Examples in Table A (above) will have an IC₅₀ in the PRMT5 assay of lessthan 200 μM. Biological activity for exemplary compounds of thedisclosure are reported in Table C.

TABLE C Biochemical and cellular potency (in Granta-519 cell line) PRMT5IC₅₀ PRMT5 sDMA IC₅₀ sDMA Prolif. IC₅₀ Prolif. Ex # μM IC₅₀_N μM IC₅₀_NμM IC₅₀_N 1 0.00075 2 0.015 1 0.04 1 2 0.0019 1 0.021 1 3 0.0016 10.0442 1 4 0.0087 1 6 0.00085 1 0.001 1 0.03 1 10 0.0011 1 12 0.0005 10.001 1 17 0.9 1 1 1 200 1 19 1.44 1 20 14.3 1 21 7.84 1 22 0.126 1 60 126 0.0048 1 0.0514 1 0.66 2 32 0.01 1 37 0.428 1 40 14.1 1 41 200 1 429.1 1 43 0.825 1 44 3.48 1 45 11.5 1 46 0.092 1 47 0.0015 3 0.031 30.075 3 49 0.229 1 50 0.017 1 9 1 51 0.404 1 53 0.0058 1 54 0.198 1 550.0008 1 0.0051 1 56 0.068 1 0.203 1 57 0.011 1 0.913 1 58 0.011 1 3.161 10 1 59 0.399 1 60 0.368 1 61 0.016 1 62 0.007 1 0.415 1 63 0.003 10.071 2 0.231 1 64 1.61 1 65 0.413 1 66 0.707 1 67 0.001 1 0.046 2 680.0009 1

FaSSIF Solubility of Example 48

Compounds were first dispersed in freshly prepared FaSSIF(http://biorelevant.com/site_media/upload/documents/How_to_make_FaSSIF_FeSSIF_and_FaSSGF.pdf)buffer in 1 mg/mL respectively, and the standard samples were preparedby preparing 1 mg/mL of test compounds in DMSO. The compounds were thensufficient mixed by vortex mixer for 30 sec, and agitated at 25° C.using 300 rpm form 4 hour in thermo mixer. After incubation, theprepared samples were centrifuged at 10000 rpm for 10 min to remove theundissolved solid, the resulting supernatants were applied to HPLC. Theactual concentrations of the compounds were evaluated by measuring thepeak area, and the solubility (S) of compounds was calculated accordingto following equation:

S=C _(smp) =C _(std)*(A _(smp) /A _(std))*(V _(std) /V _(smp))

Where C is the sample concentration in μg/mL, A is the peak area, and Vis the injection volume.Warfarin (10-25 μg/mL), Atovaquone (<2 μg/mL) and Nimesulide (100-200μg/mL) are positive controls in this experiment.Example 48 was measured to have a FaSSIF solubility of 206 μg/mL.

In Vivo Pharmacokinetic Properties of Example 47.

In a rat (SD, male, non-fasted) non-crossover PK study, Example 47 wasdosed at 1 mg/kg (DMA: 20% HPBCD=5:95, solution) via i.v. administration(N=3) and 1 mg/kg (0.5% Na CMC+0.5% Tween80, solution) via oral gauge(p.o.) (N=3). It showed average T_(1/2) of 4.1 hr, Vss of 3.1 L/kg,blood clearance of 8.8 mL/min/kg in the i.v. group; it showed averagedose normalized AUC of 3246 ng*h*kg/mL/mg and >100% of oralbioavailability in the p.o. group.

In Vivo Pharmacodynamic Effect and Tumor Growth Inhibition of Example 47in Granta-519 Mouse Xenograft Model.

Granta-519 cells was maintained in DMEM medium supplemented with 10%fetal bovine serum and 2 mM L-Glutamine at 37° C. in an atmosphere of 5%CO₂ in air. Cells in exponential growth phase were harvested and 1×10⁷cells in 0.1 mL of PBS with Matrigel (1:1) were injected subcutaneouslyat the right lower flank region of each mouse for tumor development. Thetreatments were started when the mean tumor size reaches approximately300-400 mm³. Mice were assigned into groups using StudyDirector™software (Studylog Systems, Inc. CA, USA) and one optimal randomizationdesign (generated by either Matched distribution or Stratified method)that shows minimal group to group variation in tumor volume was selectedfor group allocation. Example 47 or vehicle (0.5% Na CMC+0.5% Tween80,suspension) were administered orally (QD for Example 47, QD for vehicle)at a dose of 30 mg/kg and 50 mg/kg for 19 and 16 days, respectively.Body weights and tumor size were measured every 3 to 4 days afterrandomization. Animals were euthanized 12 hours after last dosing, andblood and tumor samples were collected for analysis.

To measure sDMA levels in tumor samples, tumors from each mouse wereweighted and homogenized in RIPA buffer supplemented with proteaseinhibitor (cOmplete™, EDTA-free Protease Inhibitor Cocktail, Roche).Lysate were centrifuged at 14,000 rpm for 30 min at 4° C. to removedebris. Total protein concentrations of lysate were determined by BCAassay (ThermoFisher Scientific, Catalog #: 23225). Equal amount of totalproteins from each tumor were separated on SDS-PAGE gel, and sDMA levelswere determined by WB as described previously.

Following this protocol, Example 47 showed an average of 46% (N=5) tumorgrowth inhibition at 30 mg/kg with body weight loss of 1%; an average of79% tumor growth inhibition of at 50 mg/kg with body weight loss of 8%.It also showed >90% inhibition of sDMA at 30 mg/kg and no detectablesDMA at 50 mg/kg.

In addition, the present disclosure is directed to the followingaspects:

-   -   1. A compound of Formula I:

-   -   or a pharmaceutically acceptable salt or solvate thereof;        wherein    -   R¹ is —C₀-C₆alk-C₁-C₆alkyl, —C₀-C₆alk-C₁-C₆haloalkyl,        —C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₆alk-S—C₁-C₆alkyl,        —C₁-C₆alk-S—C₁-C₆alk-CO₂H, —C₁-C₆alk-aryl, —C₁-C₆alk-O-aryl,        —C₁-C₆alk-NH-aryl, —C₁-C₆alk-S-aryl, —C₀-C₆alk-heteroaryl,        —C₁-C₆alk-O-heteroaryl, —C₁-C₆alk-S-heteroaryl, or        —C₁-C₆alk-NH-heteroaryl;    -   R² is —C₁-C₆alkyl, —C₁-C₆haloalkyl, —C₂-C₆alkenyl, or        —C₂-C₆alkynyl;    -   R³ is H, halo, NH₂, or —C₁-C₆alkyl;    -   R⁴ is halo, —C₁-C₆alkyl, —C₁-C₆alk-O—C₁-C₆alkyl, —NR⁶R^(6′),        —NHCONR⁶R^(6′), —NHC(S)NR⁶R^(6′)—NH—O—R⁶, or —NH—NR⁶R^(6′);    -   R⁵ is H, halo, —C₁-C₆alkyl, —C₁-C₆haloalkyl, —C₂-C₆alkenyl,        —C₂-C₆alkynyl, or —C₁-C₆alk-OH; and    -   R⁶ and R^(6′) are each independently H, C₁-C₆alkyl, or        —C₁-C₆alk-OC₁-C₆alkyl, or R⁶ and R^(6′), together with the atom        to which they are attached, form a C₂-C₆heterocycloalkyl ring.    -   2. The compound of aspect 1 wherein R¹ is        —C₁-C₆alk-O-heteroaryl.    -   3. The compound of aspect 2 wherein the —C₁-C₆alk-O-heteroaryl        is ((2-amino-3-bromoquinolin-7-yl)oxy)methyl,        ((2-amino-3-chloroquinolin-7-yl)oxy)methyl,        ((2-amino-3-fluoroquinolin-7-yl)oxy)methyl,        ((2-((cyclopropylmethyl)amino)quinolin-7-yl)oxy)methyl,        ((2-(methylamino)quinolin-7-yl)oxy)methyl,        ((2-aminoquinolin-7-yl)oxy)methyl, ((indol-6-yl) oxy)methyl, or        ((indazol-6-yl)oxy)methyl.    -   4. The compound of aspect 1 wherein R₁ is        —C₁-C₆alk-S-heteroaryl.    -   5. The compound of aspect 4 wherein the —C₁-C₆alk-S-heteroaryl        is ((2-amino-3-bromoquinolin-7-yl)thio)methyl,        ((2-amino-3-chloroquinolin-7-yl)thio)methyl,        ((2-amino-3-fluoroquinolin-7-yl)thio)methyl,        ((2-((cyclopropylmethyl)amino)quinolin-7-yl)thio)methyl,        ((2-(methylamino)quinolin-7-yl)thio)methyl,        ((2-aminoquinolin-7-yl)thio)methyl, ((indol-6-yl) thio)methyl,        or ((indazol-6-yl)thio)methyl.    -   6. The compound of aspect 1 wherein R₁ is        —C₁-C₆alk-NH-heteroaryl.    -   7. The compound of aspect 6 wherein the —C₁-C₆alk-NH-heteroaryl        is ((2-amino-3-bromoquinolin-7-yl)amino)methyl,        ((2-amino-3-chloroquinolin-7-yl)amino)methyl,        ((2-amino-3-fluoroquinolin-7-yl)amino)methyl,        ((2-((cyclopropylmethyl)amino)quinolin-7-yl)amino)methyl,        ((2-(methylamino)quinolin-7-yl)amino)methyl,        ((2-aminoquinolin-7-yl)amino)methyl, ((indol-6-yl) amino)methyl,        or ((indazol-6-yl)amino)methyl.    -   8. The compound of aspect 1 wherein R₁ is —C₀-C₆alk-heteroaryl.    -   9. The compound of aspect 8 wherein the —C₀-C₆alk-heteroaryl is        2-(2-amino-3-bromoquinolin-7-yl)ethyl,        2-(2-amino-3-chloroquinolin-7-yl)ethyl,        2-(2-amino-3-fluoroquinolin-7-yl)ethyl,        2-(2-((cyclopropylmethyl)amino)quinolin-7-yl)ethyl,        2-(2-(methylamino)quinolin-7-yl)ethyl,        2-(2-aminoquinolin-7-yl)ethyl, (indol-6-yl)ethyl, or        (indazol-6-yl)ethyl.    -   10. The compound of aspect 1 wherein R¹ is        —C₁-C₆alk-S—C₁-C₆alkyl.    -   11. The compound of aspect 10 wherein the —C₁-C₆alk-S—C₁-C₆alkyl        is —CH₂—S—CH₃.    -   12. The compound of aspect 1 wherein R¹ is        —C₁-C₆alk-S—C₁-C₆alk-CO₂H.    -   13. The compound of aspect 12 wherein the        —C₁-C₆alk-S—C₁-C₆alk-CO₂H is CH₂—S—CH₂CH₂CH(NH₂)—CO₂H.    -   14. The compound of aspect 1 wherein R¹ is        —C₁-C₆alk-O—C₁-C₆alkyl.    -   15. The compound of aspect 14 wherein the —C₁-C₆alk-O—C₁-C₆alkyl        is —CH₂—O—CH₃.    -   16. The compound of aspect 1 wherein R¹ is —C₁-C₆alk-O-aryl.    -   17. The compound of aspect 16 wherein the —C₁-C₆alk-O-aryl is        —CH₂—O-phenyl, —CH₂—O-difluorophenyl, —CH₂—O-3,4-difluorophenyl,        —CH₂—O-4-chlorophenyl, —CH₂—O-3-chloro-4-fluorophenyl,        —CH₂—O-4-chloro-3-fluorophenyl, —CH₂—O-dichlorophenyl,        —CH₂—O-3,4-dichlorophenyl, —CH₂—O-3-methyl-4-chlorophenyl,        —CH₂—O-3-fluoro-4-trifluoromethylphenyl,        —CH₂—O-3-(aminomethyl)phenyl, or —CH₂—O-3-(urea)phenyl.    -   18. The compound of aspect 1 wherein R¹ is        —C₀-C₆alk-C₁-C₆haloalkyl.    -   19. The compound of aspect 18 wherein the        —C₀-C₆alk-C₁-C₆haloalkyl is —CH₂—Cl.    -   20. The compound of aspect 1 wherein R¹ is —C₁-C₆alk-aryl.    -   21. The compound of aspect 20 wherein the —C₁-C₆alk-aryl is        —CH₂-difluorophenyl, —CH₂-3,4-difluorophenyl,        —CH₂-4-chlorophenyl, —CH₂-3-chloro-4-fluorophenyl,        —CH₂-4-chloro-3-fluorophenyl, —CH₂-dichlorophenyl,        —CH₂-3,4-dichlorophenyl, —CH₂-3-methyl-4-chlorophenyl,        —CH₂-3-fluoro-4-trifluoromethylphenyl, —CH(OH)-4-chlorophenyl,        —CH(OH)-3,4-dichlorophenyl, —CH(OH)-3,4-difluorophenyl,        —CH(OH)-3-fluoro-4-chlorophenyl,        —CH(OH)-3-chloro-4-fluorophenyl,        —CH(OH)-3-methyl-4-chlorophenyl,        —CH(OH)-3-fluoro-4-trifluoromethylphenyl, —CH(F)-4-chlorophenyl,        —CH(F)-3,4-dichlorophenyl, —CH(F)-3,4-difluorophenyl,        —CH(F)-3-fluoro-4-chlorophenyl, —CH(F)-3-chloro-4-fluorophenyl,        —CH(F)-3-methyl-4-chlorophenyl,        —CH(F)-3-fluoro-4-trifluoromethylphenyl,        —CH(NH₂)-4-chlorophenyl, —CH(NH₂)-3,4-dichlorophenyl,        —CH(NH₂)-3,4-difluorophenyl, —CH(NH₂)-3-fluoro-4-chlorophenyl,        —CH(NH₂)-3-chloro-4-fluorophenyl,        —CH(NH₂)-3-methyl-4-chlorophenyl,        —CH(NH₂)-3-fluoro-4-trifluoromethylphenyl,        —CH(Me)-4-chlorophenyl, —CH(Me)-3,4-dichlorophenyl,        —CH(Me)-3,4-difluorophenyl, —CH(Me)-3-fluoro-4-chlorophenyl,        —CH(Me)-3-chloro-4-fluorophenyl,        —CH(Me)-3-methyl-4-chlorophenyl,        —CH(Me)-3-fluoro-4-trifluoromethylphenyl,        —C(Me)(OH)-4-chlorophenyl, —C(Me)(OH)-3,4-dichlorophenyl,        —C(Me)(OH)-3,4-difluorophenyl,        —C(Me)(OH)-3-fluoro-4-chlorophenyl,        —C(Me)(OH)-3-chloro-4-fluorophenyl,        —CH(Me)(OH)-3-methyl-4-chlorophenyl, or        —CH(Me)(OH)-3-fluoro-4-trifluoromethylphenyl.    -   22. The compound of any one of aspects 1 to 21 wherein R² is        —C₁-C₆alkyl, preferably methyl.    -   23. The compound of any one of aspects 1 to 21 wherein R² is        —C₁-C₆haloalkyl, preferably —CF₃.    -   24. The compound of any one of aspects 1 to 21 wherein R² is        —C₂-C₆alkenyl, preferably vinyl.    -   25. The compound of any one of aspects 1 to 21 wherein R² is        —C₂-C₆alkynyl, preferably ethynyl.    -   26. The compound of any one of aspects 1 to 25 wherein R³ is H.    -   27. The compound of any one of aspects 1 to 26 wherein R⁴ is        —C₁-C₆alkyl.    -   28. The compound of any one of aspects 1 to 26 wherein R⁴ is        —C₁-C₆alk-O—C₁-C₆alkyl.    -   29. The compound of any one of aspects 1 to 26 wherein R⁴ is        chloro, fluoro, bromo, or iodo.    -   30. The compound of any one of aspects 1 to 26 wherein R⁴ is        —NR⁶R^(6′), wherein R⁶ and R^(6′) are preferably both H.    -   31. The compound of any one of aspects 1 to 26 wherein R⁴ is        —NHCONR⁶R^(6′), wherein R⁶ and R^(6′) are preferably both        —C₁-C₆alkyl.    -   32. The compound of any one of aspects 1 to 26 wherein R⁴ is        NHC(S)NR⁶R^(6′.)    -   33. The compound of any one of aspects 1 to 26 wherein R⁴ is        —NH—O—R⁶, wherein R⁶ is preferably —C₁-C₆alkyl.    -   34. The compound of any one of aspects 1 to 26 wherein R⁴ is        —NH—NR⁶R^(6′), wherein R⁶ and R^(6′) are preferably both        —C₁-C₆alkyl or wherein R⁶ is preferably —C₁-C₆alkyl and R^(6′)        is preferably H.    -   35. The compound of any one of aspects 1 to 34 wherein R⁵ is H.    -   36. The compound of any one of aspects 1 to 34 wherein R⁵ is        halo, preferably fluoro.    -   37. The compound of any one of aspects 1 to 34 wherein R⁵ is        —C₁-C₆alkyl.    -   38. The compound of any one of aspects 1 to 34 wherein R⁵ is        —C₁-C₆haloalkyl.    -   39. The compound of any one of aspects 1 to 34 wherein R⁵ is        —C₂-C₆alkenyl, preferably vinyl.    -   40. The compound of any one of aspects 1 to 34 wherein R⁵ is        —C₂-C₆alkynyl, preferably ethynyl.    -   41. The compound of any one of aspects 1 to 34 wherein R⁵ is        —C₁-C₆alk-OH.    -   42. A pharmaceutical composition comprising a compound according        to any one of aspects 1 to 41 and a pharmaceutically acceptable        excipient.    -   43. A method of inhibiting a protein arginine methyltransferase        5 (PRMT5) enzyme, comprising: contacting the PRMT5 enzyme with        an effective amount of a compound of any one of any one of        aspects 1 to 41.    -   44. A method of treating a disease or disorder associated with        aberrant PRMT5 activity in a subject comprising administering to        the subject, a compound of any one of aspects 1 to 41.    -   45. The method of aspect 44, wherein the disease or disorder        associated with aberrant PRMT5 activity is breast cancer, lung        cancer, pancreatic cancer, prostate cancer, colon cancer,        ovarian cancer, uterine cancer, cervical cancer, leukemia such        as acute myeloid leukemia (AML), acute lymphocytic leukemia,        chronic lymphocytic leukemia, chronic myeloid leukemia, hairy        cell leukemia, myelodysplasia, myeloproliferative disorders,        acute myelogenous leukemia (AML), chronic myelogenous leukemia        (CML), mastocytosis, chronic lymphocytic leukemia (CLL),        multiple myeloma (MM), myelodysplastic syndrome (MDS),        epidermoid cancer, or hemoglobinopathies such as b-thalassemia        and sickle cell disease (SCD).    -   46. A compound of Formula I:

-   -   or a pharmaceutically acceptable salt or solvate thereof;        wherein    -   R¹ is —C₀-C₆alk-C₁-C₆alkyl, —C₀-C₆alk-C₁-C₆haloalkyl,        —C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₆alk-S—C₁-C₆alkyl,        —C₁-C₆alk-S—C₁-C₆alk-CO₂H, —C₁-C₆alk-aryl, —C₁-C₆alk-O-aryl,        —C₁-C₆alk-NH-aryl, —C₁-C₆alk-S-aryl, —C₀-C₆alk-heteroaryl,        —C₁-C₆alk-O-heteroaryl, —C₁-C₆alk-S-heteroaryl,        —C₁-C₆alk-NH-heteroaryl, or —C(O)NH-aryl;    -   R² is —C₁-C₆alkyl, —C₁-C₆haloalkyl, —C₂-C₆alkenyl, or        —C₂-C₆alkynyl;    -   R³ is H, halo, NH₂, or —C₁-C₆alkyl;    -   R⁴ is halo, —C₁-C₆alkyl, —C₁-C₆alk-O—C₁-C₆alkyl, —NR⁶R^(6′),        —NHCONR⁶R^(6′), —NHC(S)NR⁶R^(6′), —NH—O—R⁶, or —NH—NR⁶R^(6′);    -   R⁵ is H, halo, —C₁-C₆alkyl, —C₁-C₆haloalkyl, —C₂-C₆alkenyl,        —C₂-C₆alkynyl, or —C₁-C₆alk-OH; and    -   R⁶ and R^(6′) are each independently H, C₁-C₆alkyl, or        —C₁-C₆alk-OC₁-C₆alkyl;    -   or R⁶ and R^(6′), together with the atom to which they are        attached, form a C₃-C₆heterocycloalkyl ring.    -   47. The compound of aspect 46 wherein R¹ is        —C₁-C₆alk-O-heteroaryl.    -   48. The compound of aspect 47 wherein the —C₁-C₆alk-O-heteroaryl        is ((2-amino-3-bromoquinolin-7-yl)oxy)methyl,        ((2-amino-3-chloroquinolin-7-yl)oxy)methyl,        ((2-amino-3-fluoroquinolin-7-yl)oxy)methyl,        ((2-((cyclopropylmethyl)amino)quinolin-7-yl)oxy)methyl,        ((2-(methylamino)quinolin-7-yl)oxy)methyl,        ((2-aminoquinolin-7-yl)oxy)methyl, ((indol-6-yl) oxy)methyl,        2-(methoxyamino)quinolin-7-yl)oxy)methyl,        ((quinolin-7-yl)oxy)methyl, or ((indazol-6-yl)oxy)methyl.    -   49. The compound of aspect 46 wherein R₁ is        —C₁-C₆alk-S-heteroaryl.    -   50. The compound of aspect 49 wherein the —C₁-C₆alk-S-heteroaryl        is ((2-amino-3-bromoquinolin-7-yl)thio)methyl,        ((2-amino-3-chloroquinolin-7-yl)thio)methyl,        ((2-amino-3-fluoroquinolin-7-yl)thio)methyl,        ((2-((cyclopropylmethyl)amino)quinolin-7-yl)thio)methyl,        ((2-(methylamino)quinolin-7-yl)thio)methyl,        ((2-aminoquinolin-7-yl)thio)methyl, ((indol-6-yl) thio)methyl,        or ((indazol-6-yl)thio)methyl.    -   51. The compound of aspect 46 wherein R₁ is        —C₁-C₆alk-NH-heteroaryl.    -   52. The compound of aspect 51 wherein the        —C₁-C₆alk-NH-heteroaryl is        ((2-amino-3-bromoquinolin-7-yl)amino)methyl,        ((2-amino-3-chloroquinolin-7-yl)amino)methyl,        ((2-amino-3-fluoroquinolin-7-yl)amino)methyl,        ((2-((cyclopropylmethyl)amino)quinolin-7-yl)amino)methyl,        ((2-(methylamino)quinolin-7-yl)amino)methyl,        ((2-aminoquinolin-7-yl)amino)methyl, ((indol-6-yl) amino)methyl,        or ((indazol-6-yl)amino)methyl.    -   53. The compound of aspect 46 wherein R¹ is        —C₀-C₆alk-heteroaryl.    -   54. The compound of aspect 53 wherein the —C₀-C₆alk-heteroaryl        is 2-(2-amino-3-bromoquinolin-7-yl)ethyl,        2-(2-amino-3-chloroquinolin-7-yl)ethyl,        2-(2-amino-3-fluoroquinolin-7-yl)ethyl,        2-(2-((cyclopropylmethyl)amino)quinolin-7-yl)ethyl,        2-(2-(methylamino)quinolin-7-yl)ethyl,        2-(2-aminoquinolin-7-yl)ethyl, (indol-6-yl)ethyl, or        (indazol-6-yl)ethyl.    -   55. The compound of aspect 46 wherein R¹ is        —C₁-C₆alk-S—C₁-C₆alkyl.    -   56. The compound of aspect 55 wherein the —C₁-C₆alk-S—C₁-C₆alkyl        is —CH₂—S—CH₃.    -   57. The compound of aspect 46 wherein R¹ is        —C₁-C₆alk-S—C₁-C₆alk-CO₂H.    -   58. The compound of aspect 57 wherein the        —C₁-C₆alk-S—C₁-C₆alk-CO₂H is —CH₂—S—CH₂CH₂CH(NH₂)—CO₂H.    -   59. The compound of aspect 46 wherein R¹ is        —C₁-C₆alk-O—C₁-C₆alkyl.    -   60. The compound of aspect 59 wherein the —C₁-C₆alk-O—C₁-C₆alkyl        is —CH₂—O—CH₃.    -   61. The compound of aspect 46 wherein R¹ is —C₁-C₆alk-O-aryl.    -   62. The compound of aspect 61 wherein the —C₁-C₆alk-O-aryl is        —CH₂—O-phenyl, —CH₂—O-difluorophenyl, —CH₂—O-3,4-difluorophenyl,        —CH₂—O-4-chlorophenyl, —CH₂—O-3-chloro-4-fluorophenyl,        —CH₂—O-4-chloro-3-fluorophenyl, —CH₂—O-dichlorophenyl,        —CH₂—O-3,4-dichlorophenyl, —CH₂—O-3-methyl-4-chlorophenyl,        —CH₂—O-3-fluoro-4-trifluoromethylphenyl,        —CH₂—O-3-(aminomethyl)phenyl, or —CH₂—O-3-(urea)phenyl.    -   63. The compound of aspect 46 wherein R¹ is        —C₀-C₆alk-C₁-C₆haloalkyl.    -   64. The compound of aspect 63 wherein the        —C₀-C₆alk-C₁-C₆haloalkyl is —CH₂—Cl.    -   65. The compound of aspect 46 wherein R¹ is —C₁-C₆alk-aryl.    -   66. The compound of aspect 65 wherein the —C₁-C₆alk-aryl is        —CH₂-difluorophenyl, —CH₂-3,4-difluorophenyl,        —CH₂-4-chlorophenyl, —CH₂-3-chloro-4-fluorophenyl,        —CH₂-4-chloro-3-fluorophenyl, —CH₂-dichlorophenyl,        —CH₂-3,4-dichlorophenyl, —CH₂-3-methyl-4-chlorophenyl,        —CH₂-3-fluoro-4-trifluoromethylphenyl,        benzo[d][1,3]dioxazol-5-ylmethyl, —CH(OH)-4-chlorophenyl,        —CH(OH)-3,4-dichlorophenyl, —CH(OH)-3,4-difluorophenyl,        —CH(OH)-3-fluoro-4-chlorophenyl,        —CH(OH)-3-chloro-4-fluorophenyl,        —CH(OH)-3-methyl-4-chlorophenyl,        —CH(OH)-3-fluoro-4-trifluoromethylphenyl,        —CH(OH)-benzo[d][1,3]dioxazol-5-yl, —CH(F)-4-chlorophenyl,        —CH(F)-3,4-dichlorophenyl, —CH(F)-3,4-difluorophenyl,        —CH(F)-3-fluoro-4-chlorophenyl, —CH(F)-3-chloro-4-fluorophenyl,        —CH(F)-3-methyl-4-chlorophenyl,        —CH(F)-3-fluoro-4-trifluoromethylphenyl,        —CH(F)-benzo[d][1,3]dioxazol-5-yl, —CH(NH₂)-4-chlorophenyl,        —CH(NH₂)-3,4-dichlorophenyl, —CH(NH₂)-3,4-difluorophenyl,        —CH(NH₂)-3-fluoro-4-chlorophenyl,        —CH(NH₂)-3-chloro-4-fluorophenyl,        —CH(NH₂)-3-methyl-4-chlorophenyl,        —CH(NH₂)-3-fluoro-4-trifluoromethylphenyl,        —CH(NH₂)-benzo[d][1,3]dioxazol-5-yl, —CH(Me)-4-chlorophenyl,        —CH(Me)-3,4-dichlorophenyl, —CH(Me)-3,4-difluorophenyl,        —CH(Me)-3-fluoro-4-chlorophenyl,        —CH(Me)-3-chloro-4-fluorophenyl,        —CH(Me)-3-methyl-4-chlorophenyl,        —CH(Me)-3-fluoro-4-trifluoromethylphenyl,        —CH(Me)-benzo[d][1,3]dioxazol-5-yl, —C(Me)(OH)-4-chlorophenyl,        —C(Me)(OH)-3,4-dichlorophenyl, —C(Me)(OH)-3,4-difluorophenyl,        —C(Me)(OH)-3-fluoro-4-chlorophenyl,        —C(Me)(OH)-3-chloro-4-fluorophenyl,        —CH(Me)(OH)-3-methyl-4-chlorophenyl,        —C(Me)(OH)-benzo[d][1,3]dioxazol-5-yl, or        —CH(Me)(OH)-3-fluoro-4-trifluoromethylphenyl.    -   67. The compound of aspect 66, wherein the —C₁-C₆alk-aryl is        —CH(OH)-3,4-dichlorophenyl.    -   68. The compound of aspect 46 wherein R¹ is —C(O)NH-aryl.    -   69. The compounds of aspect 46 wherein the —C(O)NH-aryl is        3-(aminomethyl)phenyl-NH—C(O)—.    -   70. The compound of any one of aspects 46 to 69 wherein R² is        —C₁-C₆alkyl, preferably methyl.    -   71. The compound of any one of aspects 46 to 69 wherein R² is        —C₁-C₆haloalkyl, preferably —CF₃.    -   72. The compound of any one of aspects 46 to 69 wherein R² is        —C₂-C₆alkenyl, preferably vinyl.    -   73. The compound of any one of aspects 46 to 69 wherein R² is        —C₂-C₆alkynyl, preferably ethynyl.    -   74. The compound of any one of aspects 46 to 73 wherein R¹ is H.    -   75. The compound of any one of aspects 46 to 74 wherein R⁴ is        —C₁-C₆alkyl, preferably methyl.    -   76. The compound of any one of aspects 46 to 74 wherein R⁴ is        —C₁-C₆alk-O—C₁-C₆alkyl.    -   77. The compound of any one of aspects 46 to 74 wherein R⁴ is        chloro, fluoro, bromo, or iodo.    -   78. The compound of any one of aspects 46 to 74 wherein R⁴ is        —NR⁶R^(6′), wherein R⁶ and R^(6′) are preferably both H.    -   79. The compound of any one of aspects 46 to 74 wherein R⁴ is        —NHCONR⁶R^(6′), wherein R⁶ and R^(6′) are preferably both        —C₁-C₆alkyl.    -   80. The compound of any one of aspects 46 to 74 wherein R⁴ is        —NHC(S)NR⁶R^(6′. 81). The compound of any one of aspects 46 to        74 wherein R⁴ is —NH—O—R⁶, wherein R⁶ is preferably —C₁-C₆alkyl.    -   82. The compound of any one of aspects 46 to 74 wherein R⁴ is        —NH—NR⁶R^(6′), wherein R⁶ and R^(6′) are preferably both        —C₁-C₆alkyl or wherein R⁶ is preferably —C₁-C₆alkyl and R^(6′)        is preferably H.    -   83. The compound of any one of aspects 46 to 82 wherein R⁵ is H.    -   84. The compound of any one of aspects 46 to 82 wherein R¹ is        halo, preferably fluoro.    -   85. The compound of any one of aspects 46 to 82 wherein R¹ is        —C₁-C₆alkyl.    -   86. The compound of any one of aspects 46 to 82 wherein R⁵ is        —C₁-C₆haloalkyl.    -   87. The compound of any one of aspects 46 to 82 wherein R⁵ is        —C₂-C₆alkenyl, preferably vinyl.    -   88. The compound of any one of aspects 46 to 82 wherein R⁵ is        —C₂-C₆alkynyl, preferably ethynyl.    -   89. The compound of any one of aspects 46 to 82 wherein R¹ is        —C₁-C₆alk-OH.    -   90. A pharmaceutical composition comprising a compound according        to any one of aspects 46 to 89 and a pharmaceutically acceptable        excipient.    -   91. A method of inhibiting a protein arginine methyltransferase        5 (PRMT5) enzyme, comprising: contacting the PRMT5 enzyme with        an effective amount of a compound of any one of any one of        aspects 46 to 89.    -   92. A method of treating a disease or disorder associated with        aberrant PRMT5 activity in a subject comprising administering to        the subject, a compound of any one of aspects 46 to 89.    -   93. The method of aspect 92, wherein the disease or disorder        associated with aberrant PRMT5 activity is breast cancer, lung        cancer, pancreatic cancer, prostate cancer, colon cancer,        ovarian cancer, uterine cancer, cervical cancer, leukemia such        as acute myeloid leukemia (AML), acute lymphocytic leukemia,        chronic lymphocytic leukemia, chronic myeloid leukemia, hairy        cell leukemia, myelodysplasia, myeloproliferative disorders,        acute myelogenous leukemia (AML), chronic myelogenous leukemia        (CML), mastocytosis, chronic lymphocytic leukemia (CLL),        multiple myeloma (MM), myelodysplastic syndrome (MDS),        epidermoid cancer, or hemoglobinopathies such as b-thalassemia        and sickle cell disease (SCD).    -   94. A compound of Formula I:

-   -   or a pharmaceutically acceptable salt or solvate thereof;        wherein    -   R¹ is —C₀-C₆alk-C₁-C₆alkyl, —C₀-C₆alk-C₁-C₆haloalkyl,        —C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₆alk-S—C₁-C₆alkyl,        —C₁-C₆alk-S—C₁-C₆alk-CO₂H, —C₁-C₆alk-aryl, —C₁-C₆alk-O-aryl,        —C₁-C₆alk-NH-aryl, —C₁-C₆alk-S-aryl, —C₀-C₆alk-heteroaryl,        —C₁-C₆alk-O-heteroaryl, —C₁-C₆alk-S-heteroaryl,        —C₁-C₆alk-NH-heteroaryl, or —C(O)NH-aryl;    -   R² is —C₁-C₆alkyl, —C₁-C₆haloalkyl, —C₂-C₆alkenyl, or        —C₂-C₆alkynyl;    -   R³ is H, halo, NH₂, or —C₁-C₆alkyl;    -   R⁴ is halo, —C₁-C₆alkyl, —C₁-C₆alk-O—C₁-C₆alkyl, —NR⁶R^(6′),        —NHCONR⁶R^(6′), —NHC(S)NR⁶R^(6′), —NH—O—R⁶, or —NH—NR⁶R^(6′);    -   R⁵ is H, halo, —C₁-C₆alkyl, —C₁-C₆haloalkyl, —C₂-C₆alkenyl,        —C₂-C₆alkynyl, or —C₁-C₆alk-OH; and    -   R⁶ and R^(6′) are each independently H, C₁-C₆alkyl, or        —C₁-C₆alk-OC₁-C₆alkyl;    -   or R⁶ and R^(6′), together with the atom to which they are        attached, form a C₃-C₆heterocycloalkyl ring.    -   95. The compound of aspect 94 wherein R¹ is        —C₁-C₆alk-O-heteroaryl.    -   96. The compound of aspect 95 wherein the —C₁-C₆alk-O-heteroaryl        is ((2-amino-3-bromoquinolin-7-yl)oxy)methyl,        ((2-amino-3-chloroquinolin-7-yl)oxy)methyl,        ((2-amino-3-fluoroquinolin-7-yl)oxy)methyl,        ((2-((cyclopropylmethyl)amino)quinolin-7-yl)oxy)methyl,        ((2-(methylamino)quinolin-7-yl)oxy)methyl,        ((2-aminoquinolin-7-yl)oxy)methyl, ((indol-6-yl) oxy)methyl,        2-(methoxyamino)quinolin-7-yl)oxy)methyl,        ((quinolin-7-yl)oxy)methyl, or ((indazol-6-yl)oxy)methyl.    -   97. The compound of aspect 94 wherein R₁ is        —C₁-C₆alk-S-heteroaryl.    -   98. The compound of aspect 97 wherein the —C₁-C₆alk-S-heteroaryl        is ((2-amino-3-bromoquinolin-7-yl)thio)methyl,        ((2-amino-3-chloroquinolin-7-yl)thio)methyl,        ((2-amino-3-fluoroquinolin-7-yl)thio)methyl,        ((2-((cyclopropylmethyl)amino)quinolin-7-yl)thio)methyl,        ((2-(methylamino)quinolin-7-yl)thio)methyl,        ((2-aminoquinolin-7-yl)thio)methyl, ((indol-6-yl) thio)methyl,        or ((indazol-6-yl)thio)methyl.    -   99. The compound of aspect 94 wherein R₁ is        —C₁-C₆alk-NH-heteroaryl.    -   100. The compound of aspect 99 wherein the        —C₁-C₆alk-NH-heteroaryl is        ((2-amino-3-bromoquinolin-7-yl)amino)methyl,        ((2-amino-3-chloroquinolin-7-yl)amino)methyl,        ((2-amino-3-fluoroquinolin-7-yl)amino)methyl,        ((2-((cyclopropylmethyl)amino)quinolin-7-yl)amino)methyl,        ((2-(methylamino)quinolin-7-yl)amino)methyl,        ((2-aminoquinolin-7-yl)amino)methyl, ((indol-6-yl) amino)methyl,        or ((indazol-6-yl)amino)methyl.    -   101. The compound of aspect 94 wherein R₁ is        —C₀-C₆alk-heteroaryl.    -   102. The compound of aspect 101 wherein the —C₀-C₆alk-heteroaryl        is 2-(2-amino-3-bromoquinolin-7-yl)ethyl,        2-(2-amino-3-chloroquinolin-7-yl)ethyl,        2-(2-amino-3-fluoroquinolin-7-yl)ethyl,        2-(2-((cyclopropylmethyl)amino)quinolin-7-yl)ethyl,        2-(2-(methylamino)quinolin-7-yl)ethyl,        2-(2-aminoquinolin-7-yl)ethyl, (indol-6-yl)ethyl, or        (indazol-6-yl)ethyl.    -   103. The compound of aspect 94 wherein R¹ is        —C₁-C₆alk-S—C₁-C₆alkyl.    -   104. The compound of aspect 103 wherein the        —C₁-C₆alk-S—C₁-C₆alkyl is —CH₂—S—CH₃.    -   105. The compound of aspect 94 wherein R¹ is        —C₁-C₆alk-S—C₁-C₆alk-CO₂H.    -   106. The compound of aspect 105 wherein the        —C₁-C₆alk-S—C₁-C₆alk-CO₂H is —CH₂—S—CH₂CH₂CH(NH₂)—CO₂H.    -   107. The compound of aspect 94 wherein R¹ is        —C₁-C₆alk-O—C₁-C₆alkyl.    -   108. The compound of aspect 107 wherein the        —C₁-C₆alk-O—C₁-C₆alkyl is —CH₂—O—CH₃.    -   109. The compound of aspect 94 wherein R¹ is —C₁-C₆aIk-O-aryl.    -   110. The compound of aspect 109 wherein the —C₁-C₆alk-O-aryl is        —CH₂—O-phenyl, —CH₂—O-difluorophenyl, —CH₂—O-3,4-difluorophenyl,        —CH₂—O-4-chlorophenyl, —CH₂—O-3-chloro-4-fluorophenyl,        —CH₂—O-4-chloro-3-fluorophenyl, —CH₂—O-dichlorophenyl,        —CH₂—O-3,4-dichlorophenyl, —CH₂—O-3-methyl-4-chlorophenyl,        —CH₂—O-3-fluoro-4-trifluoromethylphenyl,        —CH₂—O-3-(aminomethyl)phenyl, or —CH₂—O-3-(urea)phenyl.    -   111. The compound of aspect 94 wherein R¹ is        —C₀-C₆alk-C₁-C₆haloalkyl.    -   112. The compound of aspect 111 wherein the        —C₀-C₆alk-C₁-C₆haloalkyl is —CH₂—Cl.    -   113. The compound of aspect 94 wherein R¹ is —C₁-C₆alk-aryl.    -   114. The compound of aspect 113 wherein the —C₁-C₆alk-aryl is        —CH₂-difluorophenyl, —CH₂-3,4-difluorophenyl,        —CH₂-4-chlorophenyl, —CH₂-3-chloro-4-fluorophenyl,        —CH₂-4-chloro-3-fluorophenyl, —CH₂-dichlorophenyl,        —CH₂-3,4-dichlorophenyl, —CH₂-3-methyl-4-chlorophenyl,        —CH₂-3-fluoro-4-trifluoromethylphenyl,        benzo[d][1,3]dioxazol-5-ylmethyl, —CH(OH)-4-chlorophenyl,        —CH(OH)-3,4-dichlorophenyl, —CH(OH)-3,4-difluorophenyl,        —CH(OH)-3-fluoro-4-chlorophenyl,        —CH(OH)-3-chloro-4-fluorophenyl,        —CH(OH)-3-methyl-4-chlorophenyl,        —CH(OH)-3-fluoro-4-trifluoromethyl phenyl,        —CH(OH)-benzo[d][1,3]dioxazol-5-yl, —CH(F)-4-chlorophenyl,        —CH(F)-3,4-dichlorophenyl, —CH(F)-3,4-difluorophenyl,        —CH(F)-3-fluoro-4-chlorophenyl, —CH(F)-3-chloro-4-fluorophenyl,        —CH(F)-3-methyl-4-chlorophenyl.        —CH(F)-3-fluoro-4-trifluoromethylphenyl,        —CH(F)-benzo[d][1,3]dioxazol-5-yl, —CH(NH₂)-4-chlorophenyl,        —CH(NH₂)-3,4-dichlorophenyl, —CH(NH₂)-3,4-difluorophenyl,        —CH(NH₂)-3-fluoro-4-chlorophenyl,        —CH(NH₂)-3-chloro-4-fluorophenyl,        —CH(NH₂)-3-methyl-4-chlorophenyl,        —CH(NH₂)-3-fluoro-4-trifluoromethylphenyl,        —CH(NH₂)-benzo[d][1,3]dioxazol-5-yl, —CH(Me)-4-chlorophenyl,        —CH(Me)-3,4-dichlorophenyl, —CH(Me)-3,4-difluorophenyl,        —CH(Me)-3-fluoro-4-chlorophenyl,        —CH(Me)-3-chloro-4-fluorophenyl, —CH(Me)-3-methyl        -4-chlorophenyl, —CH(Me)-3-fluoro-4-trifluoromethylphenyl,        —CH(Me)-benzo[d][1,3]dioxazol-5-yl, —C(Me)(OH)-4-chlorophenyl,        —C(Me)(OH)-3,4-dichlorophenyl, —C(Me)(OH)-3,4-difluorophenyl,        —C(Me)(OH)-3-fluoro-4-chlorophenyl,        —C(Me)(OH)-3-chloro-4-fluorophenyl,        —CH(Me)(OH)-3-methyl-4-chlorophenyl,        —C(Me)(OH)-benzo[d][1,3]dioxazol-5-yl, or        —CH(Me)(OH)-3-fluoro-4-trifluoromethylphenyl.    -   115. The compound of aspect 114, wherein the —C₁-C₆alk-aryl is        —CH(OH)-3,4-dichlorophenyl.    -   116. The compound of aspect 94 wherein R¹ is —C(O)NH-aryl.    -   117. The compounds of aspect 94 wherein the —C(O)NH-aryl is        3-(aminomethyl)phenyl-NH—C(O)—.    -   118. The compound of any one of aspects 94 to 117 wherein R² is        —C₁-C₆alkyl, preferably methyl.    -   119. The compound of any one of aspects 94 to 117 wherein R² is        —C₁-C₆haloalkyl, preferably —CF₃.    -   120. The compound of any one of aspects 94 to 117 wherein R² is        —C₂-C₆alkenyl, preferably vinyl.    -   121. The compound of any one of aspects 94 to 117 wherein R² is        —C₂-C₆alkynyl, preferably ethynyl.    -   122. The compound of any one of aspects 94 to 121 wherein R³ is        H.    -   123. The compound of any one of aspects 94 to 122 wherein R⁴ is        —C₁-C₆alkyl, preferably methyl.    -   124. The compound of any one of aspects 94 to 122 wherein R⁴ is        —C₁-C₆alk-O—C₁-C₆alkyl.    -   125. The compound of any one of aspects 94 to 122 wherein R⁴ is        chloro, fluoro, bromo, or iodo.    -   126. The compound of any one of aspects 94 to 122 wherein R⁴ is        —NR⁶R^(6′), wherein R⁶ and R^(6′) are preferably both H.    -   127. The compound of any one of aspects 94 to 122 wherein R⁴ is        —NHCONR⁶R^(6′), wherein R⁶ and R^(6′) are preferably both        —C₁-C₆alkyl.    -   128. The compound of any one of aspects 94 to 122 wherein R⁴ is        —NHC(S)NR⁶R^(6′. 129). The compound of any one of aspects 94 to        122 wherein R⁴ is —NH—O—R⁶, wherein R⁶ is preferably        —C₁-C₆alkyl.    -   130. The compound of any one of aspects 94 to 122 wherein R⁴ is        —NH—NR⁶R^(6′), wherein R⁶ and R^(6′) are preferably both        —C₁-C₆alkyl or wherein R⁶ is preferably —C₁-C₆alkyl and R^(6′)        is preferably H.    -   131. The compound of any one of aspects 94 to 130 wherein R⁵ is        H.    -   132. The compound of any one of aspects 94 to 130 wherein R⁵ is        halo, preferably fluoro.    -   133. The compound of any one of aspects 94 to 130 wherein R⁵ is        —C₁-C₆alkyl.    -   134. The compound of any one of aspects 94 to 130 wherein R⁵ is        —C₁-C₆haloalkyl.    -   135. The compound of any one of aspects 94 to 37 wherein R⁵ is        —C₂-C₆alkenyl, preferably vinyl.    -   136. The compound of any one of aspects 94 to 130 wherein R⁵ is        —C₂-C₆alkynyl, preferably ethynyl.    -   137. The compound of any one of aspects 94 to 130 wherein R⁵ is        —C₁-C₆alk-OH.    -   138. A pharmaceutical composition comprising a compound        according to any one of aspects 94 to 137 and a pharmaceutically        acceptable excipient.    -   139. A method of inhibiting a protein arginine methyltransferase        5 (PRMT5) enzyme, comprising: contacting the PRMT5 enzyme with        an effective amount of a compound of any one of any one of        aspects 94 to 137.    -   140. A method of treating a disease or disorder associated with        aberrant PRMT5 activity in a subject comprising administering to        the subject, a compound of any one of aspects 94 to 137.    -   141. The method of aspect 140, wherein the disease or disorder        associated with aberrant PRMT5 activity is breast cancer, lung        cancer, pancreatic cancer, prostate cancer, colon cancer,        ovarian cancer, uterine cancer, cervical cancer, leukemia such        as acute myeloid leukemia (AML), acute lymphocytic leukemia,        chronic lymphocytic leukemia, chronic myeloid leukemia, hairy        cell leukemia, myelodysplasia, myeloproliferative disorders,        acute myelogenous leukemia (AML), chronic myelogenous leukemia        (CML), mastocytosis, chronic lymphocytic leukemia (CLL),        multiple myeloma (MM), myelodysplastic syndrome (MDS),        epidermoid cancer, or hemoglobinopathies such as b-thalassemia        and sickle cell disease (SCD).    -   142. The method of aspect 140 or aspect 141, wherein the        compound is administered in combination with one or more other        agents.    -   143. A compound of Formula I:

-   -   or a pharmaceutically acceptable salt or solvate thereof;        wherein    -   R¹ is —C₀-C₆alk-C₁-C₆alkyl, —C₀-C₆alk-C₁-C₆haloalkyl,        —C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₆alk-S—C₁-C₆alkyl,        —C₁-C₆alk-S—C₁-C₆alk-CO₂H, —C₁-C₆alk-aryl, —C₁-C₆alk-O-aryl,        —C₁-C₆alk-NH-aryl, —C₁-C₆alk-S-aryl, —C₀-C₆alk-heteroaryl,        —C₁-C₆alk-O-heteroaryl, —C₁-C₆alk-S-heteroaryl,        —C₁-C₆alk-NH-heteroaryl, or —C(O)NH-aryl;    -   R² is —C₁-C₆alkyl, —C₁-C₆haloalkyl, —C₂-C₆alkenyl, or        —C₂-C₆alkynyl;    -   R³ is H, halo, NH₂, or —C₁-C₆alkyl;    -   R⁴ is H, halo, —C₁-C₆alkyl, —C₁-C₆alk-O—C₁-C₆alkyl, —NR⁶R^(6′),        —NHCONR⁶R^(6′), —NHC(S)NR⁶R^(6′), —NH—O—R⁶, or —NH—NR⁶R^(6′);    -   R¹ is H, halo, —C₁-C₆alkyl, —C₁-C₆haloalkyl, —C₂-C₆alkenyl,        —C₂-C₆alkynyl, or —C₁-C₆alk-OH; and    -   R⁶ and R^(6′) are each independently H, C₁-C₆alkyl, or        —C₁-C₆alk-OC₁-C₆alkyl;    -   or R⁶ and R^(6′), together with the atom to which they are        attached, form a C₃-C₆heterocycloalkyl ring.    -   144. The compound of aspect 143, or a pharmaceutically        acceptable salt thereof, wherein R¹ is —C₁-C₆alk-O-heteroaryl.    -   145. The compound of aspect 144, or a pharmaceutically        acceptable salt thereof, wherein the —C₁-C₆alk-O-heteroaryl is        ((2-amino-3-bromoquinolin-7-yl)oxy)methyl,        ((2-amino-3-chloroquinolin-7-yl)oxy)methyl,        ((2-amino-3-fluoroquinolin-7-yl)oxy)methyl,        ((2-((cyclopropylmethyl)amino)quinolin-7-yl)oxy)methyl,        ((2-(methylamino)quinolin-7-yl)oxy)methyl,        ((2-aminoquinolin-7-yl)oxy)methyl, ((indol-6-yl) oxy)methyl,        (2-(methoxyamino)quinolin-7-yl)oxy)methyl,        ((quinolin-7-yl)oxy)methyl,        ((3-methylimidazo[1,2-a]pyridin-7-yl)oxy)methyl, or        ((indazol-6-yl)oxy)methyl.    -   146. The compound of aspect 143, or a pharmaceutically        acceptable salt thereof, wherein R₁ is —C₁-C₆alk-S-heteroaryl.    -   147. The compound of aspect 146, or a pharmaceutically        acceptable salt thereof, wherein the —C₁-C₆alk-S-heteroaryl is        ((2-amino-3-bromoquinolin-7-yl)thio)methyl,        ((2-amino-3-chloroquinolin-7-yl)thio)methyl,        ((2-amino-3-fluoroquinolin-7-yl)thio)methyl,        ((2-((cyclopropylmethyl)amino)quinolin-7-yl)thio)methyl,        ((2-(methylamino)quinolin-7-yl)thio)methyl,        ((2-aminoquinolin-7-yl)thio)methyl, ((indol-6-yl) thio)methyl,        or ((indazol-6-yl)thio)methyl.    -   148. The compound of aspect 143, or a pharmaceutically        acceptable salt thereof, wherein R₁ is —C₁-C₆alk-NH-heteroaryl.    -   149. The compound of aspect 148, or a pharmaceutically        acceptable salt thereof, wherein the —C₁-C₆alk-NH-heteroaryl is        ((2-amino-3-bromoquinolin-7-yl)amino)methyl,        ((2-amino-3-chloroquinolin-7-yl)amino)methyl,        ((2-amino-3-fluoroquinolin-7-yl)amino)methyl,        ((2-((cyclopropylmethyl)amino)quinolin-7-yl)amino)methyl,        ((2-(methylamino)quinolin-7-yl)amino)methyl,        ((2-aminoquinolin-7-yl)amino)methyl, ((indol-6-yl) amino)methyl,        or ((indazol-6-yl)amino)methyl.    -   150. The compound of aspect 143, or a pharmaceutically        acceptable salt thereof, wherein R₁ is —C₀-C₆alk-heteroaryl.    -   151. The compound of aspect 150, or a pharmaceutically        acceptable salt thereof, wherein the —C₀-C₆alk-heteroaryl is        2-(2-amino-3-bromoquinolin-7-yl)ethyl,        2-(2-amino-3-chloroquinolin-7-yl)ethyl,        2-(2-amino-3-fluoroquinolin-7-yl)ethyl,        2-(2-((cyclopropylmethyl)amino)quinolin-7-yl)ethyl,        2-(2-(methylamino)quinolin-7-yl)ethyl,        2-(2-aminoquinolin-7-yl)ethyl, (indol-6-yl)ethyl, or        (indazol-6-yl)ethyl.    -   152. The compound of aspect 143, or a pharmaceutically        acceptable salt thereof, wherein R¹ is —C₁-C₆alk-S—C₁-C₆alkyl.    -   153. The compound of aspect 152, or a pharmaceutically        acceptable salt thereof, wherein the —C₁-C₆alk-S—C₁-C₆alkyl is        —CH₂—S—CH₃.    -   154. The compound of aspect 143, or a pharmaceutically        acceptable salt thereof, wherein R¹ is        —C₁-C₆alk-S—C₁-C₆alk-CO₂H.    -   155. The compound of aspect 154, or a pharmaceutically        acceptable salt thereof, wherein the —C₁-C₆alk-S—C₁-C₆alk-CO₂H        is —CH₂—S—CH₂CH₂CH(NH₂)—CO₂H.    -   156. The compound of aspect 143, or a pharmaceutically        acceptable salt thereof, wherein R¹ is —C₁-C₆alk-O—C₁-C₆alkyl.    -   157. The compound of aspect 156, or a pharmaceutically        acceptable salt thereof, wherein the —C₁-C₆alk-O—C₁-C₆alkyl is        —CH₂—O—CH₃.    -   158. The compound of aspect 143, or a pharmaceutically        acceptable salt thereof, wherein R¹ is —C₁-C₆alk-O-aryl.    -   159. The compound of aspect 158, or a pharmaceutically        acceptable salt thereof, wherein the —C₁-C₆alk-O-aryl is        —CH₂—O-phenyl, —CH₂—O-difluorophenyl, —CH₂—O-3,4-difluorophenyl,        —CH₂—O-4-chlorophenyl, —CH₂—O-3-chloro-4-fluorophenyl,        —CH₂—O-4-chloro-3-fluorophenyl, —CH₂—O-dichlorophenyl,        —CH₂—O-3,4-dichlorophenyl, —CH₂—O-3-methyl-4-chlorophenyl,        —CH₂—O-3-fluoro-4-trifluoromethylphenyl,        —CH₂—O-3-(aminomethyl)phenyl, or —CH₂—O-3-(urea)phenyl.    -   160. The compound of aspect 143, or a pharmaceutically        acceptable salt thereof, wherein R¹ is —C₀-C₆alk-C₁-C₆haloalkyl.    -   161. The compound of aspect 160, or a pharmaceutically        acceptable salt thereof, wherein the —C₀-C₆alk-C₁-C₆haloalkyl is        —CH₂—Cl.    -   162. The compound of aspect 143, or a pharmaceutically        acceptable salt thereof, wherein R¹ is —C₁-C₆alk-aryl.    -   163. The compound of aspect 162, or a pharmaceutically        acceptable salt thereof, wherein the —C₁-C₆alk-aryl is        —CH₂-difluorophenyl, —CH₂-3,4-difluorophenyl,        —CH₂-4-chlorophenyl, —CH₂-3-chloro-4-fluorophenyl,        —CH₂-4-chloro-3-fluorophenyl, —CH₂-dichlorophenyl,        —CH₂-3,4-dichlorophenyl, —CH₂-3-methyl-4-chlorophenyl,        —CH₂-3-fluoro-4-trifluoromethylphenyl,        benzo[d][1,3]dioxazol-5-ylmethyl,        —CH₂-(4-chloro-2-(hydroxymethyl)phenyl),        —CH₂-(4-chloro-2-(aminomethyl)phenyl),        —CH₂-(4-chloro-2-((methylamino)methyl)phenyl),        —CH₂-4-trifluoromethylphenyl, —CH₂-4-(trifluoromethoxy)phenyl,        —CH₂-4-fluoro-3-trifluoromethylphenyl, —CH₂-4-isopropylphenyl,        —CH(OH)-4-chlorophenyl, —CH(OH)-3,4-dichlorophenyl,        —CH(OH)-3,4-difluorophenyl, —CH(OH)-3-fluoro-4-chlorophenyl,        —CH(OH)-3-chloro-4-fluorophenyl, —CH(OH)-3-methyl        -4-chlorophenyl, —CH(OH)-3-fluoro-4-trifluoromethylphenyl,        —CH(OH)-benzo[d][1,3]dioxazol-5-yl,        —CH(OH)-(4-chloro-2-(hydroxymethyl)phenyl),        —CH(OH)-(4-chloro-2-(aminomethyl)phenyl),        —CH(OH)-(4-chloro-2-((methylamino)methyl)phenyl),        —CH(OH)-4-trifluoromethylphenyl,        —CH(OH)-4-(trifluoromethoxy)phenyl,        —CH(OH)-4-fluoro-3-trifluoromethylphenyl,        —CH(OH)-4-isopropylphenyl, —CH(F)-4-chlorophenyl,        —CH(F)-3,4-dichlorophenyl, —CH(F)-3,4-difluorophenyl,        —CH(F)-3-fluoro-4-chlorophenyl, —CH(F)-3-chloro-4-fluorophenyl,        —CH(F)-3-methyl-4-chlorophenyl,        —CH(F)-3-fluoro-4-trifluoromethylphenyl,        —CH(F)-benzo[d][1,3]dioxazol-5-yl,        —CH(F)-(4-chloro-2-(hydroxymethyl)phenyl),        —CH(F)-(4-chloro-2-(aminomethyl)phenyl),        —CH(F)-(4-chloro-2-((methylami no)methyl)phenyl),        —CH(F)-4-trifluoromethylphenyl,        —CH(F)-4-(trifluoromethoxy)phenyl,        —CH(F)-4-fluoro-3-trifluoromethylphenyl,        —CH(F)-4-isopropylphenyl, —CH(NH₂)-4-chlorophenyl,        —CH(NH₂)-3,4-dichlorophenyl, —CH(NH₂)-3,4-difluorophenyl,        —CH(NH-2)-3-fluoro-4-chlorophenyl,        —CH(NH₂)-3-chloro-4-fluorophenyl,        —CH(NH₂)-3-methyl-4-chlorophenyl,        —CH(NH₂)-3-fluoro-4-trifluoromethylphenyl,        —CH(NH₂)-benzo[d][1,3]dioxazol-5-yl,        —CH(NH₂)-(4-chloro-2-(hydroxymethyl)phenyl),        —CH(NH₂)-(4-chloro-2-(aminomethyl)phenyl),        —CH(NH₂)-(4-chloro-2-((methylamino)methyl)phenyl), —CH(NH₂)-4-ti        fluoromethyl phenyl, —CH(NH₂)-4-(trifluoromethoxy)phenyl,        —CH(NH₂)-4-fluoro-3-trifluoromethylphenyl,        —CH(NH₂)-4-isopropylphenyl, —CH(Me)-4-chlorophenyl,        —CH(Me)-3,4-di chlorophenyl, —CH(Me)-3,4-difluorophenyl,        —CH(Me)-3-fluoro-4-chlorophenyl,        —CH(Me)-3-chloro-4-fluorophenyl, —CH(Me)-3-methyl        -4-chlorophenyl, —CH(Me)-3-fluoro-4-trifluoromethylphenyl,        —CH(Me)-benzo[d][1,3]dioxazol-5-yl,        —CH(Me)-(4-chloro-2-(hydroxymethyl)phenyl),        —CH(Me)-(4-chloro-2-(aminomethyl)phenyl),        —CH(Me)-(4-chloro-2-((methylamino)methyl)phenyl),        —CH(Me)-4-trifluoromethylphenyl,        —CH(Me)-4-(trifluoromethoxy)phenyl,        —CH(Me)-4-fluoro-3-trifluoromethylphenyl,        —CH(Me)-4-isopropylphenyl, —C(Me)(OH)-4-chlorophenyl,        —C(Me)(OH)-3,4-dichlorophenyl, —C(Me)(OH)-3,4-difluorophenyl,        —C(Me)(OH)-3-fluoro-4-chlorophenyl,        —C(Me)(OH)-3-chloro-4-fluorophenyl,        —C(Me)(OH)-3-methyl-4-chlorophenyl,        —C(Me)(OH)-benzo[d][1,3]dioxazol-5-yl,        —C(Me)(OH)-3-fluoro-4-trifluoromethylphenyl,        —C(Me)(OH)-(4-chloro-2-(hydroxymethyl)phenyl),        —C(Me)(OH)-(4-chloro-2-(aminomethyl)phenyl),        —C(Me)(OH)-(4-chloro-2-((methylamino)methyl)phenyl),        —C(Me)(OH)-4-trifluoromethylphenyl,        —C(Me)(OH)-4-(trifluoromethoxy)phenyl,        —C(Me)(OH)-4-fluoro-3-trifluoromethylphenyl, or        —C(Me)(OH)-4-isopropylphenyl.    -   164. The compound of aspect 163, or a pharmaceutically        acceptable salt thereof, wherein the —C₁-C₆alk-aryl is        —CH(OH)-3,4-dichlorophenyl.    -   165. The compound of aspect 143, or a pharmaceutically        acceptable salt thereof, wherein R¹ is —C(O)NH-aryl.    -   166. The compounds of aspect 165, or a pharmaceutically        acceptable salt thereof, wherein the —C(O)NH-aryl is        3-(aminomethyl)phenyl-NH—C(O)—.    -   167. The compound of any one of aspects 143 to 166 wherein R² is        —C₁-C₆alkyl, preferably methyl.    -   168. The compound of any one of aspects 143 to 166 wherein R² is        —C₁-C₆haloalkyl, preferably —CF₃.    -   169. The compound of any one of aspects 143 to 166 wherein R² is        —C₂-C₆alkenyl, preferably vinyl.    -   170. The compound of any one of aspects 143 to 166 wherein R² is        —C₂-C₆alkynyl, preferably ethynyl.    -   171. The compound of any one of aspects 143 to 170 wherein R³ is        H.    -   172. The compound of any one of aspects 143 to 171 wherein R⁴ is        H.    -   173. The compound of any one of aspects 143 to 171 wherein R⁴ is        —C₁-C₆alkyl, preferably methyl.    -   174. The compound of any one of aspects 143 to 171 wherein R⁴ is        —C₁-C₆alk-O—C₁-C₆alkyl.    -   175. The compound of any one of aspects 143 to 171 wherein R⁴ is        chloro, fluoro, bromo, or iodo.    -   176. The compound of any one of aspects 143 to 171 wherein R⁴ is        —NR⁶R^(6′), wherein R⁶ and R^(6′) are preferably both H.    -   177. The compound of any one of aspects 143 to 171 wherein R⁴ is        —NHCONR⁶R^(6′), wherein R⁶ and R^(6′) are preferably both        —C₁-C₆alkyl.    -   178. The compound of any one of aspects 143 to 171 wherein R⁴ is        —NHC(S)NR⁶R^(6′. 179). The compound of any one of aspects 143 to        171 wherein R⁴ is —NH—O—R⁶, wherein R⁶ is preferably        —C₁-C₆alkyl.    -   180. The compound of any one of aspects 143 to 171 wherein R⁴ is        —NH—NR⁶R^(6′), wherein R⁶ and R^(6′) are preferably both        —C₁-C₆alkyl or wherein R⁶ is preferably —C₁-C₆alkyl and R^(6′)        is preferably H.    -   181. The compound of any one of aspects 143 to 180 wherein R¹ is        H.    -   182. The compound of any one of aspects 143 to 180 wherein R⁵ is        halo, preferably fluoro.    -   183. The compound of any one of aspects 143 to 180 wherein R⁵ is        —C₁-C₆alkyl.    -   184. The compound of any one of aspects 143 to 180 wherein R⁵ is        —C₁-C₆haloalkyl.    -   185. The compound of any one of aspects 143 to 180 wherein R⁵ is        —C₂-C₆alkenyl, preferably vinyl.    -   186. The compound of any one of aspects 143 to 180 wherein R⁵ is        —C₂-C₆alkynyl, preferably ethynyl.    -   187. The compound of any one of aspects 143 to 180 wherein R⁵ is        —C₁-C₆alk-OH.    -   188. A pharmaceutical composition comprising a compound        according to any one of aspects 143 to 187, or a        pharmaceutically acceptable salt thereof, and a pharmaceutically        acceptable excipient.    -   189. A method of inhibiting a protein arginine methyltransferase        5 (PRMT5) enzyme, comprising: contacting the PRMT5 enzyme with        an effective amount of a compound of any one of aspects 143 to        187, or a pharmaceutically acceptable salt thereof.    -   190. A method of treating a disease or disorder associated with        aberrant PRMT5 activity in a subject comprising administering to        the subject, a compound of any one of aspects 143 to 187, or a        pharmaceutically acceptable salt thereof.    -   191. The method of aspect 190, wherein the disease or disorder        associated with aberrant PRMT5 activity is breast cancer, lung        cancer, pancreatic cancer, prostate cancer, colon cancer,        ovarian cancer, uterine cancer, cervical cancer, leukemia such        as acute myeloid leukemia (AML), acute lymphocytic leukemia,        chronic lymphocytic leukemia, chronic myeloid leukemia, hairy        cell leukemia, myelodysplasia, myeloproliferative disorders,        acute myelogenous leukemia (AML), chronic myelogenous leukemia        (CML), mastocytosis, chronic lymphocytic leukemia (CLL),        multiple myeloma (MM), myelodysplastic syndrome (MDS),        epidermoid cancer, or hemoglobinopathies such as b-thalassemia        and sickle cell disease (SCD).    -   192. The method of aspect 190 or aspect 191, wherein the        compound, or a pharmaceutically acceptable salt thereof, is        administered in combination with one or more other agents.

What is claimed:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof; wherein R¹ is—C₀-C₆alk-C₁-C₆alkyl, —C₀-C₆alk-C₁-C₆haloalkyl, —C₁-C₆alk-O—C₁-C₆alkyl,—C₁-C₆alk-S—C₁-C₆alkyl, —C₁-C₆alk-S—C₁-C₆alk-CO₂H, —C₁-C₆alk-aryl,—C₁-C₆alk-O-aryl, —C₁-C₆alk-NH-aryl, —C₁-C₆alk-S-aryl,—C₀-C₆alk-heteroaryl, —C₁-C₆alk-O-heteroaryl, —C₁-C₆alk-S-heteroaryl,—C₁-C₆alk-NH-heteroaryl, or —C(O)NH-aryl; R² is —C₁-C₆alkyl,—C₁-C₆haloalkyl, —C₂-C₆alkenyl, or —C₂-C₆alkynyl; R³ is H, halo, NH₂, or—C₁-C₆alkyl; R⁴ is H, halo, —C₁-C₆alkyl, —C₁-C₆alk-O—C₁-C₆alkyl,—NR⁶R^(6′), —NHCONR⁶R^(6′), —NHC(S)NR⁶R^(6′), —NH—O—R⁶, or—NH—NR⁶R^(6′); R⁵ is H, halo, —C₁-C₆alkyl, —C₁-C₆haloalkyl,—C₂-C₆alkenyl, —C₂-C₆alkynyl, or —C₁-C₆alk-OH; and R⁶ and R^(6′) areeach independently H, C₁-C₆alkyl, or —C₁-C₆alk-OC₁-C₆alkyl; or R⁶ andR^(6′), together with the atom to which they are attached, form aC₃-C₆heterocycloalkyl ring.
 2. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is—C₁-C₆alk-O-heteroaryl.
 3. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R₁ is—C₁-C₆alk-S-heteroaryl.
 4. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is—C₁-C₆alk-NH-heteroaryl.
 5. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R₁ is—C₀-C₆alk-heteroaryl.
 6. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is —C₁-C₆alk-O-aryl.
 7. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein R₁ is—C₁-C₆alk-aryl.
 8. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is —C(O)NH-aryl.
 9. The compound ofclaim 1 wherein R² is —C₁-C₆alkyl.
 10. The compound of claim 1 whereinR² is —C₁-C₆haloalkyl.
 11. The compound of claim 1 wherein R² is—C₂-C₆alkenyl.
 12. The compound of claim 1 wherein R² is —C₂-C₆alkynyl.13. The compound of claim 1 wherein R³ is H.
 14. The compound of claim 1wherein R⁴ is H.
 15. The compound of claim 1 wherein R⁴ is —C₁-C₆alkyl.16. The compound of claim 1 wherein R⁴ is chloro, fluoro, bromo, oriodo.
 17. The compound of claim 1 wherein R⁴ is —NR⁶R^(6′), wherein R⁶and R^(6′) are both H.
 18. The compound of claim 1 wherein R⁴ is—NHCONR⁶R^(6′), wherein R⁶ and R^(6′) are both —C₁-C₆alkyl.
 19. Thecompound of claim 1 wherein R⁴ is —NH—O—R⁶, wherein R⁶ is —C₁-C₆alkyl.20. The compound of claim 1 wherein R⁴ is —NH—NR⁶R^(6′), wherein R⁶ andR^(6′) are both —C₁-C₆alkyl or wherein R⁶ is —C₁-C₆alkyl and R^(6′) ispreferably H.
 21. The compound of claim 1 wherein R⁵ is H.
 22. Thecompound of claim 1 wherein R⁵ is halo.
 23. A pharmaceutical compositioncomprising a compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.24. A method of inhibiting a protein arginine methyltransferase 5(PRMT5) enzyme, comprising: contacting the PRMT5 enzyme with aneffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 25. A method of treating a disease or disorderassociated with aberrant PRMT5 activity in a subject comprisingadministering to the subject, a compound of claim 1, or apharmaceutically acceptable salt thereof.
 26. The method of claim 25,wherein the disease or disorder associated with aberrant PRMT5 activityis breast cancer, lung cancer, pancreatic cancer, prostate cancer, coloncancer, ovarian cancer, uterine cancer, cervical cancer, leukemia suchas acute myeloid leukemia (AML), acute lymphocytic leukemia, chroniclymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia,myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia(AML), chronic myelogenous leukemia (CML), mastocytosis, chroniclymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplasticsyndrome (MDS), epidermoid cancer, or hemoglobinopathies such asb-thalassemia and sickle cell disease (SCD).
 27. The method of claim 26,wherein the compound, or a pharmaceutically acceptable salt thereof, isadministered in combination with one or more other agents.